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Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)

  • Last Modified: 10/10/2014

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Table of Contents

Introduction

Green Tea

Lycopene

Modified Citrus Pectin

Pomegranate

Selenium

Soy

Vitamin D

Vitamin E

Zyflamend

Other Prostate Health Supplements

Changes to This Summary (10/10/2014)

About This PDQ Summary

Introduction

This complementary and alternative medicine (CAM) information summary provides an overview of the use of various foods and dietary supplements for reducing the risk of developing prostate cancer or for treating prostate cancer. This summary includes the history of research, reviews of laboratory and animal studies, and results of clinical trials on the following foods or dietary supplements:

Each type of dietary supplement or food will have a dedicated section in the summary, and new topics will be added over time.

Prostate cancer is the most common noncutaneous cancer affecting men in the United States. From 2004 to 2008, the median age of diagnosis of prostate cancer was 67, and the incidence rate was 156 cases per 100,000 men per year.[1]

Many studies suggest that CAM use is common among prostate cancer patients, and the use of vitamins, supplements, and specific foods is frequently reported by these patients. For example, the Prostate CAncer Therapy Selection (PCATS) study was a prospective that study investigated men’s decision-making processes about treatment following a diagnosis of local stage prostate cancer. As part of this study, patients completed surveys regarding CAM use, and more than half of the respondents reported using one or more CAM therapies, with mind-body modalities and biologically based treatments being the most commonly used.[2]

International studies have reported similar findings. A Swedish study published in 2011 found that, overall, participants with prostate cancer were more likely to have used supplements than were healthy population-based control subjects. Supplement use was even more common among patients with the healthiest dietary patterns (e.g., high consumption of fatty fish and vegetables).[3] In a Canadian study, CAM use was reported among 39% of recently diagnosed prostate cancer patients, and the most commonly used forms of CAM were herbals, vitamins, and minerals. Within those categories, saw palmetto, vitamin E, and selenium were the most popular. The two most popular reasons for choosing CAM were to boost the immune system and to prevent recurrence.[4] According to another Canadian study, approximately 30% of survey respondents with prostate cancer reported using CAM treatments. In that study, vitamin E, saw palmetto, and lycopene were most commonly used.[5] A British study published in 2008 indicated that 25% of prostate cancer patients used CAM, with the most frequently reported interventions being low-fat diets, vitamins, and lycopene. The majority of CAM users in this study cited improving quality of life and boosting the immune system as the main reasons they used CAM.[6]

Vitamin and supplement use has also been documented in men at risk of developing prostate cancer. One study examined vitamin and supplement use in men with a family history of prostate cancer. At the time of the survey, almost 60% of the men were using vitamins or supplements. One third of the men were using vitamins and supplements that were specifically marketed for prostate health or chemoprevention (e.g., selenium, green tea, and saw palmetto).[7] A 2004 study examined herbal and vitamin supplement use in men who attended a prostate cancer screening clinic. Men who attended the screening clinic completed questionnaires about supplement use. Of the respondents, analysis revealed that a reported 70% used multivitamins, and 21% used herbal supplements.[8]

A meta-analysis published in 2008 reviewed studies that reported vitamin and mineral supplement use among cancer survivors. The results showed that, among prostate cancer survivors, vitamin or mineral use ranged from 26% to 35%.[9]

Although many prostate cancer patients use CAM treatments, they do not all disclose their CAM use to treating physicians. According to results from the PCATS study, 43% of patients discussed their CAM use with a healthcare professional.[2] In two separate studies, 58% of respondents told their doctors about their CAM usage.[4,6]

How do prostate cancer patients decide whether to use CAM or not? A qualitative study published in 2005 described results from interviews with prostate cancer patients who were CAM users or nonusers. The study identified differences in thinking patterns between the two groups and suggested that no specific theme led patients to CAM, rather a combination of ideas directed them. For example, the perception of CAM being harmless was associated with the belief that conventional medicine resulted in many negative side effects.[10] Results of a 2003 qualitative study suggest that decision making by prostate cancer patients about CAM treatments depends on both fixed (e.g., medical history) and flexible (e.g., a need to feel in control) decision factors.[11]

References
  1. National Cancer Institute: SEER Stat Fact Sheets: Prostate. Bethesda, MD: National Cancer Institute, 2011. Available online. Last accessed October 9, 2014. 

  2. McDermott CL, Blough DK, Fedorenko CR, et al.: Complementary and alternative medicine use among newly diagnosed prostate cancer patients. Support Care Cancer 20 (1): 65-73, 2012.  [PUBMED Abstract]

  3. Westerlund A, Steineck G, Bälter K, et al.: Dietary supplement use patterns in men with prostate cancer: the Cancer Prostate Sweden study. Ann Oncol 22 (4): 967-72, 2011.  [PUBMED Abstract]

  4. Eng J, Ramsum D, Verhoef M, et al.: A population-based survey of complementary and alternative medicine use in men recently diagnosed with prostate cancer. Integr Cancer Ther 2 (3): 212-6, 2003.  [PUBMED Abstract]

  5. Boon H, Westlake K, Stewart M, et al.: Use of complementary/alternative medicine by men diagnosed with prostate cancer: prevalence and characteristics. Urology 62 (5): 849-53, 2003.  [PUBMED Abstract]

  6. Wilkinson S, Farrelly S, Low J, et al.: The use of complementary therapy by men with prostate cancer in the UK. Eur J Cancer Care (Engl) 17 (5): 492-9, 2008.  [PUBMED Abstract]

  7. Bauer CM, Ishak MB, Johnson EK, et al.: Prevalence and correlates of vitamin and supplement usage among men with a family history of prostate cancer. Integr Cancer Ther 11 (2): 83-9, 2012.  [PUBMED Abstract]

  8. Barqawi A, Gamito E, O'Donnell C, et al.: Herbal and vitamin supplement use in a prostate cancer screening population. Urology 63 (2): 288-92, 2004.  [PUBMED Abstract]

  9. Velicer CM, Ulrich CM: Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review. J Clin Oncol 26 (4): 665-73, 2008.  [PUBMED Abstract]

  10. Singh H, Maskarinec G, Shumay DM: Understanding the motivation for conventional and complementary/alternative medicine use among men with prostate cancer. Integr Cancer Ther 4 (2): 187-94, 2005.  [PUBMED Abstract]

  11. Boon H, Brown JB, Gavin A, et al.: Men with prostate cancer: making decisions about complementary/alternative medicine. Med Decis Making 23 (6): 471-9, 2003 Nov-Dec.  [PUBMED Abstract]

Green Tea



Overview

This section contains the following key information:

  • All tea originates from the Camellia sinensis (L.) Kuntze plant, and the methods by which the leaves are processed determine the type of tea produced. For green tea, the leaves are steamed and dried.

  • Some research suggests that green tea may have a protective effect against cardiovascular disease and against various forms of cancer, including prostate cancer.

  • Catechins are polyphenol compounds in tea that are associated with many of tea’s proposed health benefits.

  • Epigallocatechin gallate (EGCG), the most abundant catechin in tea, acts as an androgen antagonist and can suppress prostate cancer cell proliferation, suppress production of prostate-specific antigen (PSA) by prostate cancer cells, and increase prostate cancer cell death in vitro .

  • Results from one in vitro study showed that prostate cancer cells were less susceptible to radiation -induced apoptosis when exposed to EGCG 30 minutes before radiation exposure.

  • Oral intake of either a green tea catechin solution or EGCG alone was associated with reduced development of prostate cancer in studies with transgenic adenocarcinoma of the mouse prostate (TRAMP) mice.

  • Epidemiologic studies of Japanese men have generally not shown a relationship between reported green tea consumption and prostate cancer development, but at least one study has shown an association with the development of advanced prostate cancer.

  • Results from a small placebo-controlled study of green tea catechins in men with high-grade prostatic intraepithelial neoplasia (HGPIN) showed a statistically significant decrease in the development of prostate cancer among men who were randomly assigned to receive the catechin supplement. A larger, multicenter, randomized trial is now under way.

  • Studies of orally administered mixtures of tea catechins in men with prostate cancer have begun to provide information about biologic effects in this setting but are too preliminary to draw conclusions about clinical effectiveness.

  • Green tea has been well tolerated in clinical studies of prostate cancer patients, with the most common side effects being mild gastrointestinal symptoms.

General Information and History

Sailors first brought tea to England in 1644, although tea has been popular in Asia since ancient times. After water, tea is the most consumed beverage in the world.[1] Tea originates from the C. sinensis plant, and the methods by which the leaves are processed determine the type of tea produced. Green tea is not fermented but is made by an enzyme deactivation step where intensive heat (i.e., roasting the freshly collected tea leaves in a wok or, historically, steaming the leaves) is applied to preserve the tea's polyphenols (catechins) and freshness. In contrast, the enzyme catalyzed polymerization and oxidation of catechins and other components produces darker colored black tea.[2] Oolong, a third major type of tea, contains polyphenols that are partially oxidized.[1]

The English word “tea” has its origins in China. Ch'a is the Mandarin word for “tea.” In the dialect spoken in the southern Chinese province of Fujian, the word for “tea” was pronounced “tay.” This term was borrowed by European traders who bought tea at the southern Chinese ports, and it evolved into tea (English), thé (French), and Tee (German). “Tea” is also used to describe infusions of medicinal herbs, such as sage and calamint.[3] In this PDQ information summary, “tea” refers to the leaves of the C. sinensis plant or the beverage brewed from those leaves.

Some observational and interventional studies suggest that green tea may have a protective effect against cardiovascular disease,[4] and there is evidence that green tea may protect against various forms of cancer.[5] Many of the health benefits associated with tea have been attributed to polyphenols. Catechins compose most of the polyphenols found in tea; of these, epigallocatechin-3-gallate (EGCG) has been the most widely researched.[6] Tea leaves also contain considerable amounts of oligomeric catechins, commonly known as oligomeric proanthocyanidins. Together with the catechin monomers, they constitute the green tea polyphenols (GTPs). GTP composition varies widely, depending on processing and source of the tea leaves.

Preclinical/Animal Studies

In vitro studies

Laboratory experiments have increased our understanding of the reported associations between green tea and prostate cancer. For example, in one study, prostate cancer cells treated with EGCG (concentrations, 0–80 μM) demonstrated suppressed cell proliferation and decreased levels of PSA protein and mRNA in the presence or absence of androgen.[7]

In a 2011 study, human prostate cancer cells were treated initially with EGCG (concentrations, 1.5–7.5 μM) and then with radiation. The results showed that exposing cells to EGCG for 30 minutes before radiation significantly reduced apoptosis, compared to radiation alone.[8]

In another study, prostate cancer cells treated with EGCG (0–50 μM) exhibited dose-dependent decreases in cellular proliferation and increases in extracellular signal-regulated kinase (ERK) 1/2 activity. To further examine the effect of EGCG on the ERK 1/2 pathway, cells were treated with EGCG (0–50 μM) and a mitogen-activated protein kinase (MEK) inhibitor or phosphoinositide-3 kinase (PI3K) inhibitor. Inhibition of MEK did not prevent ERK 1/2 upregulation, although the increase in ERK 1/2 after EGCG treatment was partially inhibited with the PI3K inhibitor. These findings suggest that EGCG may prevent prostate cancer cell proliferation by increasing the activity of ERK 1/2 via a MEK-independent, PI3K-dependent mechanism.[9]

According to a 2010 study, EGCG treatment (20–120 μM) resulted in changes in expression levels of 40 genes in prostate cancer cells, including a fourfold downregulation of inhibitor of DNA binding 2 (ID2; a protein involved in cell proliferation and survival). In addition, forced expression of ID2 in cells treated with 80 μM EGCG resulted in reduced apoptosis, suggesting that EGCG may cause cell death via an ID2-related mechanism.[10]

Advances in nanotechnology—“nanochemoprevention”—may result in more effective administration of EGCG to men at risk of prostate cancer. Prostate cancer cells were treated with EGCG-loaded (100 μM EGCG) nanoparticles or free EGCG. Although both treatments decreased cell proliferation and induced apoptosis, the nanoparticle treatment had a greater effect at a lower concentration than did free EGCG. This finding suggests that using a nanoparticle delivery system for EGCG may increase its bioavailability and improve its chemopreventive actions.[11] In another study, EGCG (30 μM) was encapsulated in nanoparticles that contained polymers targeting prostate-specific membrane antigen (PSMA). Prostate cancer cells treated with this intervention exhibited decreases in proliferation; however, the intervention did not affect nonmalignant control cells. The results suggest that this delivery system may be effective for selective targeting of prostate cancer cells.[12]

Research also suggests that glutathione-S-transferase pi (GSTP1) may be a tumor suppressor and that hypermethylation of certain regions of this gene (i.e., CpG islands) may be a molecular marker of prostate cancer. Increased methylation leads to silencing of the gene. A set of experiments investigated the effects of green tea polyphenols on GSTP1 expression. Treatment of different types of prostate cancer cells with green tea polyphenols (1–10 μg/mL Polyphenon E) resulted in re-expression of GSTP1 by reversing hypermethylation and by reducing expression of methyl-CpG binding domain (MBD) proteins, which bind to methylated DNA. These results indicate that green tea polyphenols may have chemopreventive effects via actions on gene-silencing processes.[13]

The results of a 2011 study suggested that green tea polyphenols may exert anticancer effects by inhibiting histone deacetylases (HDAC). Class I HDACs are often overexpressed in various cancers, including prostate cancer. Treatment of human prostate cancer cells with green tea polyphenols (10–80 μg/mL Polyphenon E) resulted in decreased class I HDAC activity and increased expression of Bax, a proapoptotic protein.[14]

Owing to the high concentrations of tea polyphenols used in some of the in vitro experiments, results should be interpreted with caution. Studies in humans have indicated that blood levels of EGCG are 0.1 to 0.6 µM after consumption of two to three cups of green tea and that drinking seven to nine cups of green tea results in EGCG blood levels still lower than 1 μM.[15,16] A 1 μM solution of EGCG would contain 0.458 μg of EGCG per mL.

Animal studies

Animal models have been used in numerous studies investigating the effects of green tea on prostate cancer. In one study, TRAMP mice were given access to water or green tea catechin-treated water (0.3% green tea catechin solution; this exposure mimics human consumption of 6 cups of green tea daily). After 24 weeks, water-fed TRAMP mice had developed prostate cancer whereas mice treated with green tea catechins showed only PIN lesions, suggesting that green tea catechins may help delay the development of prostate tumors. Furthermore, the results showed that mice treated with green tea catechins had lower prostate tissue levels of MCM7 (a protein that is important in DNA replication and that is up-regulated during cancer progression) than mice treated with water, suggesting that green tea may delay prostate cancer progression by inhibiting MCM7 expression.[17] In another study, castrated mice were injected with prostate cancer cells and then treated daily with intraperitoneal injections of 1 mg EGCG or vehicle. Treatment with EGCG resulted in reductions in tumor volume and decreases in serum PSA levels compared to vehicle treatment. These results provide a rationale for the exploration of EGCG treatment in patients with advanced prostate cancer.[7]

In a 2011 study, EGCG was shown to be an androgen antagonist; when added to prostate cancer cells, EGCG physically interacted with the androgen receptor’s ligand-binding domain. In addition, mice implanted with tumor cells and treated with EGCG (intraperitoneal injections of 1 mg EGCG, 3/week) exhibited less androgen receptor protein expression than did mice that were treated with vehicle. These findings suggest that the beneficial effects of green tea may be a result of EGCG’s inhibitory actions on the androgen receptor, and, because androgen receptor signaling is generally intact in hormone-refractory and hormone-sensitive prostate cancer, green tea has the potential to be useful in both forms of the disease.[18]

The age at which green tea consumption begins may determine how effective it is in prostate cancer prevention. In a 2009 study, TRAMP mice were started on a green tea polyphenol intervention (0.1% green tea polyphenols in drinking water) at various ages (meant to represent different stages of prostate cancer development).[19] The results showed that, although all of the green tea–fed mice exhibited longer tumor-free survival than did water-fed control mice, there was an advantage for the mice that were fed with green tea the longest. These findings suggest that green tea may be most beneficial in men diagnosed with early prostatic intraepithelial neoplasia (PIN) lesions, men who are at high risk of developing prostate cancer, or men who are undergoing watchful waiting.[19] In another study, EGCG treatment (0.06% EGCG in drinking water; this exposure mimics human consumption of 6 cups of green tea daily) was initiated in TRAMP mice at age 12 or 28 weeks. EGCG treatment suppressed HGPIN in mice treated at age 12 weeks; however, EGCG did not prevent prostate cancer development in mice that began treatment at age 28 weeks.[20] In a third study, TRAMP and wild-type mice were administered green tea polyphenols in drinking water (0.05% green tea polyphenols in drinking water) starting at 4 weeks or 25 weeks after weaning. Consumption of GTP did not affect prostate pathology, but there were systemic effects. Young animals who received green tea exhibited lower plasma lipid levels, regardless of genotype, than did older animals who received green tea. These findings suggest that age and metabolic capacity may influence the chemopreventive effects of green tea polyphenols.[21] Using the TRAMP mice model,[22] one study demonstrated that oral infusion of GTP extract at a human-achievable dose (equivalent to 6 cups of green tea per day) significantly delayed primary tumor incidence and tumor burden, as assessed sequentially by magnetic resonance imaging, decreased prostate weight (64% of baseline) and genitourinary weight (72%), inhibited serum insulin-like growth factor -1 (IGF-I), restored insulin-like growth factor binding protein-3 (IGFBP-3) levels, and produced marked reduction in the protein expression of proliferating cell nuclear antigen in the GTP-fed TRAMP mice, compared with water-fed TRAMP mice. Furthermore, GTP consumption caused significant apoptosis, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of development, progression, and metastasis to distant organ sites.

These disparate observations in preclinical trials may be attributed to the pharmacokinetic properties of the individual catechin (i.e., EGCG vs. whole green tea polyphenols). Compared with green tea polyphenols, EGCG has relatively low oral bioavailability, possibly because of slow absorption and high metabolic clearance by the liver.[23,24] Other potential confounders may include dosage, method of infusion, duration of intervention, and timing of castration, all of which may influence the markers of progression and the antioxidant property of EGCG. Oral administration of GTP, versus pure EGCG, in drinking water to TRAMP mice may have contributed to higher systemic exposure compared with gavage administration. This may explain the protective effects observed,[19,22,25,26] compared with studies that failed to demonstrate similar effect.[23] Overall, these preclinical studies have informed the design and evaluation of GTP in prostate cancer prevention and treatment.

Animal Safety Studies

In the National Cancer Institute's (NCI) Division of Cancer Prevention (DCP) 9-month oral toxicity study, Polyphenon E, a botanical drug substance containing a mixture of catechins, was administered (200, 500, or 1,000 mg/kg/day) to fasted male and female beagle dogs. The study was terminated prematurely because of excessive loss of animals due to morbidity and mortality in all treatment groups. Gross necropsy revealed therapy-induced lesions in the gastrointestinal tract, liver, kidneys, reproductive organs, and hematopoietic tissues of treated male and female dogs. An investigation to determine the cause of the toxicity is ongoing; administration of the agent to fasted dogs may have caused increased toxicity in the 9-month versus 13-week NCI DCP-sponsored follow-up study. In the 13-week follow-up study, the no-observed-adverse-effect–level was greater than 600 mg/kg/day of Polyphenon E. Nonspecific toxicity and a tenfold reduction in the maximum tolerated dose in fasted versus fed beagle dogs were also seen in another published 13-week toxicity study using a purified GTE containing less than 77% EGCG.[27] However, in the follow-up NCI DCP-sponsored study in fed versus fasted dogs using several Polyphenon E formulations, no deaths occurred; numerous biochemical endpoints are currently being evaluated.

Human Studies

Epidemiologic studies

The relationship between green tea intake and prostate cancer has been examined in numerous clinical studies.

A 2011 meta-analysis examined the consumption of green and black tea and prostate cancer risk. For green tea, seven observational studies were identified, and most were from Asia. The results indicated a statistically significant inverse association between green tea consumption and prostate cancer risk in the three case control studies, but no association was found in the four cohort studies. For black tea, no association was found between black tea consumption and prostate cancer risk. The inconsistent results reported in these population studies may be attributed to confounding factors that include consumption of salted or very hot tea, geographical location, tobacco and alcohol use, and other dietary differences.[28-32] Overall, findings from population studies suggest that green tea may help protect against prostate cancer in Asian populations.[33] Currently, there are no epidemiological studies in other populations examining the association between green tea consumption and prostate cancer risk or protection from risk. With the increasing consumption of green tea worldwide, including by the U.S. population, emerging data from ongoing studies will further contribute to defining the cancer preventive activity of green tea or green tea catechins.

Safety Studies

The safety of tea and tea compounds is supported by centuries of consumption by the human population. In four phase I, single-dose and multidose studies targeting healthy volunteers who took a botanical drug substance containing a mixture of catechins, Polyphenon E containing a dose range of 200 to 1200 mg EGCG was well tolerated.[34-37] Adverse effects have generally been mild, with no serious adverse events reported. Adverse effects reported with a possible relationship to the study drug included asthenia, headache, abdominal pain, chest pain, diarrhea, dyspepsia, eructation, flatulence, nausea, vomiting, dizziness, vasodilation, and rash. No grade 3 or higher events were reported with a possible relationship to study drug. Grade 2 events reported with a possible relationship to study drug included asthenia, headache, abdominal pain, dyspepsia, nausea, and rash. The most frequent events in completed studies that at times were considered drug-related included headache, nausea, abdominal pain, diarrhea, dyspepsia, dizziness, and asthenia.[34] Gastrointestinal adverse effects were usually mild, seen most often in the fasting condition and at the highest dose level. Onset of gastrointestinal events typically occurred within 2 to 3 hours of dosing and resolved within 2 hours. Headaches and fatigue were not dose-related and may have been related to abstinence from caffeine or other procedure-related stresses.

In recent years, oral consumption of varying doses and compositions of green tea extracts (GTEs) has been associated with several instances of hepatotoxicity.[27,38-40] Most affected patients were women, and many were consuming GTEs for the purpose of weight loss. Although hepatotoxicity in most cases resolved within 4 months of stopping GTE, there have been cases of positive rechallenge and liver failure requiring liver transplantation. One report described a case of acute liver failure that required transplantation in a woman who consumed green tea extract capsules.[39] The capsules contained Polyphenon 70A and 120 mg green tea extract. Because no other causal relationship could be identified, the treating physicians concluded that the fulminant liver failure experienced by this patient was most likely related to the consumption of over-the-counter GTE weight-loss supplements. In addition, the sale of an ethanolic GTE sold as a weight-reduction aid was suspended in 2003 after reports associated hepatotoxicity (four cases in Spain and nine cases in France) with its use.[40] Time to onset of hepatotoxicity following ingestion of GTEs ranged from several days to several months. Increased oral bioavailability occurs when GTEs are administered on an empty stomach after an overnight fast. Increased toxicity, including hepatotoxicity, is observed when Polyphenon E or EGCG is administered to fasted dogs.[27] Therefore, the FDA Division of Drug Oncology Products has recommended that Polyphenon E be taken with food by subjects participating in clinical studies. In addition, subjects should have liver function tests performed while on treatment.

Green tea has been well tolerated in clinical studies of patients with prostate cancer.[41-43] In a 2005 study, the most commonly reported side effects were gastrointestinal symptoms. These symptoms were mild for all but two participants, who experienced severe anorexia and moderate dyspnea.[44] There is evidence that long-term consumption of ten or more cups of green tea daily may cause headaches, which may be related to the caffeine content in the tea.[45]

Intervention studies

Prevention

In a single-center Italian study, 60 men diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN) were randomly assigned to receive green tea catechin capsules (600 mg green tea catechins daily) or a placebo every day for 1 year. After 6 months, 6 of the 30 men in the placebo group were diagnosed with prostate cancer, whereas none of the 30 subjects in the green tea catechin group were diagnosed with prostate cancer. After 1 year, nine men in the placebo group and one man in the green tea catechin group were diagnosed with prostate cancer (P < .01). These findings suggest that green tea catechins may help prevent prostate cancer in groups at high risk for the disease.[41] In 2008, follow-up results to this study were published, indicating that the inhibitory effects of green tea catechins on prostate cancer progression were long-lasting.[46] A larger, multicenter, randomized trial (NCT00596011) in the United States studied men with either HGPIN or atypical small acinar proliferation (ASAP) who received a green tea catechin mixture (Polyphenon E, 200 mg, twice a day).[47] Results are pending.

Treatment

Preoperative therapy

In one study, patients scheduled for radical prostatectomy were randomly assigned to drink green tea, black tea, or a soda five times a day for 5 days. Bioavailable tea polyphenols were found in prostate samples of the patients who had consumed green tea and black tea. In addition, prostate cancer cells were treated with participants’ serum, and the results showed that there was less proliferation using post-tea serum than using serum obtained before the tea intervention.[48] In another study, prostate cancer patients scheduled to undergo radical prostatectomy were randomly assigned to drink six cups of green tea or water daily for 3 to 6 weeks before surgery. An analysis of prostate tissue obtained from the green tea drinkers revealed that both methylated and nonmethylated forms of EGCG are found in the prostate following a short-term treatment with green tea, with 48% of EGCG in the methylated form. Methylated forms of EGCG are not as effective as EGCG in inhibiting cell proliferation and inducing apoptosis in prostate cancer cells, suggesting that methylation status of EGCG may affect the chemopreventive properties of green tea. Methylation status may be determined by polymorphisms of the catechol -O-methyltransferase (COMT; the molecule that methylates EGCG) gene.[42]

In another open-label, phase II clinical study, prostate cancer patients scheduled for radical prostatectomy consumed four Polyphenon E tablets containing tea polyphenols, including EGCG, daily (providing 800 mg EGCG daily) until surgery. The Polyphenon E treatment had a positive effect on a number of prostate cancer biomarkers, including PSA, vascular endothelial growth factor (VEGF), and IGF-1 (a protein associated with increased risk of prostate cancer).[43]

In a 2011 study, 50 prostate cancer patients were randomly assigned to receive Polyphenon E (800 mg EGCG) or a placebo daily for 3 to 6 weeks before surgery. Treatment with Polyphenon E resulted in greater decreases in serum levels of PSA and IGF-1 than did treatment with placebo, but these differences were not statistically significant. The findings of this study suggest that the chemopreventive effects of green tea polyphenols may be through indirect means and that longer intervention studies may be needed.[49]

Advanced prostate cancer

In a small, single-arm study, hormone-refractory prostate cancer patients received capsules of green tea extract twice daily (375 mg polyphenols daily) for up to 5 months. Although the green tea intervention was well tolerated by most study participants, no patient had a PSA response (i.e., at least 50% decrease from baseline), and all 19 patients were deemed to have progressive disease within 1 to 5 months.[44]

In a 2003 study, patients with androgen-independent metastatic prostate cancer consumed 6 g of powdered green tea extract daily for up to 4 months. Among 42 participants, 1 patient exhibited a 50% decrease in serum PSA level compared to baseline, but this response was not sustained beyond 2 months. Green tea was well tolerated by most study participants. However, six episodes of grade 3 toxicity occurred, involving insomnia, confusion, and fatigue. These results suggest that, in patients with advanced prostate cancer, green tea may have limited benefits.[50]

Current Clinical Trials

Check NCI’s list of cancer clinical trials for CAM clinical trials on green tea for prostate cancer and green tea extract for prostate cancer that are actively enrolling patients.

General information about clinical trials is also available from the NCI Web site.

References
  1. Landau JM, Lambert JD, Yang CS: Green tea. In: Heber D, Blackburn GL, Go VLW, et al., eds.: Nutritional Oncology. 2nd ed. Burlington, Ma: Academic Press, 2006, pp 597-606. 

  2. Yang CS, Wang H: Mechanistic issues concerning cancer prevention by tea catechins. Mol Nutr Food Res 55 (6): 819-31, 2011.  [PUBMED Abstract]

  3. Trepardoux F, Delaveau P: [Origin of the word tea, and its extension to designate different hot infused drinks]. Rev Hist Pharm (Paris) 47 (322): 247-53, 1999.  [PUBMED Abstract]

  4. Deka A, Vita JA: Tea and cardiovascular disease. Pharmacol Res 64 (2): 136-45, 2011.  [PUBMED Abstract]

  5. Yang CS, Wang H, Li GX, et al.: Cancer prevention by tea: Evidence from laboratory studies. Pharmacol Res 64 (2): 113-22, 2011.  [PUBMED Abstract]

  6. Sang S, Lambert JD, Ho C, et al.: Green tea polyphenols. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 402-10. 

  7. Chuu CP, Chen RY, Kokontis JM, et al.: Suppression of androgen receptor signaling and prostate specific antigen expression by (-)-epigallocatechin-3-gallate in different progression stages of LNCaP prostate cancer cells. Cancer Lett 275 (1): 86-92, 2009.  [PUBMED Abstract]

  8. Thomas F, Holly JM, Persad R, et al.: Green tea extract (epigallocatechin-3-gallate) reduces efficacy of radiotherapy on prostate cancer cells. Urology 78 (2): 475.e15-21, 2011.  [PUBMED Abstract]

  9. Albrecht DS, Clubbs EA, Ferruzzi M, et al.: Epigallocatechin-3-gallate (EGCG) inhibits PC-3 prostate cancer cell proliferation via MEK-independent ERK1/2 activation. Chem Biol Interact 171 (1): 89-95, 2008.  [PUBMED Abstract]

  10. Luo KL, Luo JH, Yu YP: (-)-Epigallocatechin-3-gallate induces Du145 prostate cancer cell death via downregulation of inhibitor of DNA binding 2, a dominant negative helix-loop-helix protein. Cancer Sci 101 (3): 707-12, 2010.  [PUBMED Abstract]

  11. Rocha S, Generalov R, Pereira Mdo C, et al.: Epigallocatechin gallate-loaded polysaccharide nanoparticles for prostate cancer chemoprevention. Nanomedicine (Lond) 6 (1): 79-87, 2011.  [PUBMED Abstract]

  12. Sanna V, Pintus G, Roggio AM, et al.: Targeted biocompatible nanoparticles for the delivery of (-)-epigallocatechin 3-gallate to prostate cancer cells. J Med Chem 54 (5): 1321-32, 2011.  [PUBMED Abstract]

  13. Pandey M, Shukla S, Gupta S: Promoter demethylation and chromatin remodeling by green tea polyphenols leads to re-expression of GSTP1 in human prostate cancer cells. Int J Cancer 126 (11): 2520-33, 2010.  [PUBMED Abstract]

  14. Thakur VS, Gupta K, Gupta S: Green tea polyphenols causes cell cycle arrest and apoptosis in prostate cancer cells by suppressing class I histone deacetylases. Carcinogenesis 33 (2): 377-84, 2012.  [PUBMED Abstract]

  15. Thakur VS, Gupta K, Gupta S: The chemopreventive and chemotherapeutic potentials of tea polyphenols. Curr Pharm Biotechnol 13 (1): 191-9, 2012.  [PUBMED Abstract]

  16. Tachibana H: Molecular basis for cancer chemoprevention by green tea polyphenol EGCG. Forum Nutr 61: 156-69, 2009.  [PUBMED Abstract]

  17. McCarthy S, Caporali A, Enkemann S, et al.: Green tea catechins suppress the DNA synthesis marker MCM7 in the TRAMP model of prostate cancer. Mol Oncol 1 (2): 196-204, 2007.  [PUBMED Abstract]

  18. Siddiqui IA, Asim M, Hafeez BB, et al.: Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. FASEB J 25 (4): 1198-207, 2011.  [PUBMED Abstract]

  19. Adhami VM, Siddiqui IA, Sarfaraz S, et al.: Effective prostate cancer chemopreventive intervention with green tea polyphenols in the TRAMP model depends on the stage of the disease. Clin Cancer Res 15 (6): 1947-53, 2009.  [PUBMED Abstract]

  20. Harper CE, Patel BB, Wang J, et al.: Epigallocatechin-3-Gallate suppresses early stage, but not late stage prostate cancer in TRAMP mice: mechanisms of action. Prostate 67 (14): 1576-89, 2007.  [PUBMED Abstract]

  21. Teichert F, Verschoyle RD, Greaves P, et al.: Plasma metabolic profiling reveals age-dependency of systemic effects of green tea polyphenols in mice with and without prostate cancer. Mol Biosyst 6 (10): 1911-6, 2010.  [PUBMED Abstract]

  22. Gupta S, Hastak K, Ahmad N, et al.: Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci U S A 98 (18): 10350-5, 2001.  [PUBMED Abstract]

  23. Suttie A, Nyska A, Haseman JK, et al.: A grading scheme for the assessment of proliferative lesions of the mouse prostate in the TRAMP model. Toxicol Pathol 31 (1): 31-8, 2003 Jan-Feb.  [PUBMED Abstract]

  24. Zaveri NT: Green tea and its polyphenolic catechins: medicinal uses in cancer and noncancer applications. Life Sci 78 (18): 2073-80, 2006.  [PUBMED Abstract]

  25. Khan N, Mukhtar H: Cancer and metastasis: prevention and treatment by green tea. Cancer Metastasis Rev 29 (3): 435-45, 2010.  [PUBMED Abstract]

  26. Khan N, Adhami VM, Mukhtar H: Review: green tea polyphenols in chemoprevention of prostate cancer: preclinical and clinical studies. Nutr Cancer 61 (6): 836-41, 2009.  [PUBMED Abstract]

  27. Kapetanovic IM, Crowell JA, Krishnaraj R, et al.: Exposure and toxicity of green tea polyphenols in fasted and non-fasted dogs. Toxicology 260 (1-3): 28-36, 2009.  [PUBMED Abstract]

  28. Clinical development plan: tea extracts. Green tea polyphenols. Epigallocatechin gallate. J Cell Biochem Suppl 26: 236-57, 1996.  [PUBMED Abstract]

  29. Bushman JL: Green tea and cancer in humans: a review of the literature. Nutr Cancer 31 (3): 151-9, 1998.  [PUBMED Abstract]

  30. Higdon JV, Frei B: Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr 43 (1): 89-143, 2003.  [PUBMED Abstract]

  31. Ahn WS, Yoo J, Huh SW, et al.: Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur J Cancer Prev 12 (5): 383-90, 2003.  [PUBMED Abstract]

  32. Montague JA, Butler LM, Wu AH, et al.: Green and black tea intake in relation to prostate cancer risk among Singapore Chinese. Cancer Causes Control 23 (10): 1635-41, 2012.  [PUBMED Abstract]

  33. Zheng J, Yang B, Huang T, et al.: Green tea and black tea consumption and prostate cancer risk: an exploratory meta-analysis of observational studies. Nutr Cancer 63 (5): 663-72, 2011.  [PUBMED Abstract]

  34. Chow HH, Cai Y, Alberts DS, et al.: Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E. Cancer Epidemiol Biomarkers Prev 10 (1): 53-8, 2001.  [PUBMED Abstract]

  35. Chow HH, Hakim IA, Vining DR, et al.: Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of Polyphenon E in healthy individuals. Clin Cancer Res 11 (12): 4627-33, 2005.  [PUBMED Abstract]

  36. Pisters KM, Newman RA, Coldman B, et al.: Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol 19 (6): 1830-8, 2001.  [PUBMED Abstract]

  37. Chow HH, Cai Y, Hakim IA, et al.: Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res 9 (9): 3312-9, 2003.  [PUBMED Abstract]

  38. Bonkovsky HL: Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med 144 (1): 68-71, 2006.  [PUBMED Abstract]

  39. Molinari M, Watt KD, Kruszyna T, et al.: Acute liver failure induced by green tea extracts: case report and review of the literature. Liver Transpl 12 (12): 1892-5, 2006.  [PUBMED Abstract]

  40. Pedrós C, Cereza G, García N, et al.: [Liver toxicity of Camellia sinensis dried etanolic extract]. Med Clin (Barc) 121 (15): 598-9, 2003.  [PUBMED Abstract]

  41. Bettuzzi S, Brausi M, Rizzi F, et al.: Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res 66 (2): 1234-40, 2006.  [PUBMED Abstract]

  42. Wang P, Aronson WJ, Huang M, et al.: Green tea polyphenols and metabolites in prostatectomy tissue: implications for cancer prevention. Cancer Prev Res (Phila) 3 (8): 985-93, 2010.  [PUBMED Abstract]

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  49. Nguyen MM, Ahmann FR, Nagle RB, et al.: Randomized, double-blind, placebo-controlled trial of polyphenon E in prostate cancer patients before prostatectomy: evaluation of potential chemopreventive activities. Cancer Prev Res (Phila) 5 (2): 290-8, 2012.  [PUBMED Abstract]

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Lycopene



Overview

This section contains the following key information:

General Information and History

Lycopene is a carotenoid, a natural pigment made by plants, which helps to protect plants from stress,[1] and it also transfers light energy during photosynthesis.[2] Lycopene is found in a number of fruits and vegetables, including apricots, guavas, and watermelon, but the majority of lycopene consumed in the United States is from tomato-based products.[1] The bioavailability of lycopene is greater in processed tomato products, such as tomato paste and tomato puree, than it is in raw tomatoes.[3] When ingested, lycopene is broken down into a number of metabolites and is thought to have various biological functions, including antioxidant capabilities and a role in gap-junction communication.[4]

There is evidence that dietary fat may help increase the absorption of carotenoids, including lycopene. In one experiment, healthy volunteers consumed mixed-vegetable salads with nonfat, low-fat, or full-fat salad dressing. Analysis of blood samples indicated that eating full-fat salad dressing led to more carotenoid absorption than eating low-fat or nonfat dressing.[5] Results of a randomized study published in 2005 revealed that cooking diced tomatoes with olive oil significantly increased lycopene absorption compared with cooking tomatoes without olive oil.[6] According to one study,[7] there was no difference in plasma lycopene levels following consumption of tomatoes mixed with olive oil or tomatoes mixed with sunflower oil, suggesting that absorption of lycopene may not be dependent on the type of oil used. However, this same study found that combining olive oil, but not sunflower oil, with tomatoes resulted in greater plasma antioxidant activity.

Lycopene has been investigated for its role in chronic diseases, including cardiovascular disease and cancer. Numerous epidemiological studies suggest that lycopene may help prevent cardiovascular disease, although some interventional studies have shown mixed results.[3] Lycopene may protect against cardiovascular disease by decreasing cholesterol synthesis and increasing the degradation of low-density lipoproteins.[8] A number of in vitro and in vivo studies suggest that lycopene may also be protective against cancers of the skin, breast, lung, and liver.[9] However, epidemiological studies reported to date have yielded inconsistent findings regarding lycopene's potential in reducing cancer risk. The few human intervention trials have been small and generally focused on intermediate endpoints and thus have not been definitive.[2,10]

In 2004, the FDA received two petitions for qualified health claims regarding tomatoes, lycopene, and reduced cancer risk. In a 2007 review, the FDA concluded there was not enough evidence to support a claim that lycopene helps reduce cancer risk. The FDA found there was no evidence of a link between tomato consumption and lung, colorectal, breast, cervical, or endometrial cancers, and there was limited evidence for an association between tomato consumption and reduced risks of prostate, ovarian, gastric, and pancreatic cancers.[11]

Preclinical/Animal Studies

In vitro studies

Many in vitro studies have been conducted examining a link between lycopene and prostate cancer.

Treating normal human prostate epithelial cells with lycopene resulted in dose-dependent growth inhibition, indicating that inhibition of prostate cell proliferation may be one way lycopene may lower the risk of prostate cancer.[12]

In addition, treating prostate cancer cells with lycopene resulted in a significant decrease in the number of lycopene-treated cells in S phase of the cell cycle, suggesting that lycopene may lower cell proliferation by altering cell-cycle progression. Moreover, apo-12’-lycopenal, a lycopene metabolite, also reduced prostate cancer cell proliferation and may also modulate cell-cycle progression.[13]

Some studies have suggested that cancer cells have altered cholesterol-biosynthesis pathways. Treating prostate cancer cells with lycopene resulted in dose-dependent decreases in 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (the rate-limiting enzyme in cholesterol synthesis), total cholesterol, and cell growth, and an increase in apoptosis. However, adding mevalonate prevented the growth-inhibitory effects of lycopene, indicating that the mevalonate pathway may be important to the anticancer activity of lycopene.[14] Lycopene may also affect cholesterol levels in prostate cancer cells by activating the peroxisome proliferator-activated receptor gamma (PPARγ)-liver X receptor alpha (LXRα)-ATP-binding cassette, subfamily 1 (ABCA1) pathway, which leads to decreased cholesterol levels and may ultimately result in decreased cell proliferation. ABCA1 mediates cholesterol efflux, and PPARγ has been shown to inhibit the growth and differentiation of prostate cancer cells. In one study, treating prostate cancer cells with lycopene resulted in increased expression of PPARγ, LXRα, and ABCA1 as well as lower total cholesterol. In addition, when the cells were treated with a PPARγ antagonist, cell proliferation increased while treating cells with a combination of the PPARγ antagonist and lycopene decreased cell proliferation.[15]

Adding lycopene to medium containing the LNCaP human prostate adenocarcinoma cell line resulted in decreased DNA synthesis and inhibition of androgen-receptor gene-element activity and expression.[16] In a study that examined the physiologically relevant concentration of lycopene (2 mmol/L) or placebo for 48 hours on protein expression in human primary prostatic epithelial cells, proteins that were significantly upregulated or downregulated following lycopene exposure were those proteins involved in antioxidant responses, cytoprotection, apoptosis, growth inhibition, androgen receptor signaling, and the AKT /mTOR cascade. These data are consistent with previous studies, suggesting that lycopene can prevent malignant transformation in human prostatic epithelial cells at the stages of cancer initiation, promotion, and/or progression.[17]

Some studies have assessed possible beneficial interactions between lycopene and conventional cancer therapies. In one such study, various types of prostate cancer cells were treated with a combination of lycopene and docetaxel, a drug used to treat patients with castration -resistant prostate cancer, or each drug alone. The combination treatment inhibited proliferation in four of five cell lines to a greater extent than did treatment with docetaxel alone. The findings suggest that the mechanism for these effects may involve the IGF-1 receptor (IGF-1R) pathway.[18]

Animal studies

In a chemoprevention study, 59 transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed diets supplemented with tomato paste or lycopene beadlets (both preparations contained 28 mg lycopene/kg chow). Mice that received lycopene beadlets exhibited a larger reduction in prostate cancer incidence compared with control mice than mice supplemented with tomato paste, suggesting that lycopene beadlets may provide greater chemopreventive effects than tomato paste.[19]

Ketosamines are carbohydrate derivatives formed when food is dehydrated. In one study, FruHis (a ketosamine in dehydrated tomatoes) combined with lycopene resulted in greater growth inhibition of implanted rat prostate cancer cells than did lycopene or FruHis alone. In addition, in a N-methyl-N-nitrosourea (NMU)/testosterone-induced prostate carcinogenesis model, rats fed a tomato paste and FruHis diet had longer survival times than rats fed only with tomato paste or tomato powder.[20]

Lycopene has also been studied for potential therapeutic effects in xenograft studies. In one study, athymic nude mice were injected with human androgen-independent prostate cancer cells and were treated with either lycopene (4 mg/kg body weight or 16 mg/kg body weight) or beta-carotene (16 mg/kg body weight). Supplementing mice with lycopene or beta carotene resulted in decreased tumor growth.[21] In an in vitro study, the investigators demonstrated the effect of lycopene in androgen-independent prostate cancer cell lines.[22] In another study, nude mice were injected with human prostate cancer cells and treated with intraperitoneal injections of docetaxel, lycopene (15 mg/kg per day) administered via gavage, or a combination of both. Mice exhibited longer survival times and smaller tumors when treated with a combination of docetaxel and lycopene than when they were treated with docetaxel alone.[18]

Human Studies

Epidemiologic studies

Several epidemiologic studies have assessed potential associations between lycopene intake and prostate cancer incidence.

Epidemiological studies have demonstrated that populations with high intake of dietary lycopene have lower risks of prostate cancer.[11-16] Prospective and case control studies have shown lycopene to be significantly lower in the serum and tissue of patients with cancer than in controls,[11,18-21] while other studies have failed to demonstrate such a connection.[23]

An association between lycopene serum concentration and risk of cancer was also examined in men participating in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study in Finland. In this prospective cohort study, an inverse association between lycopene levels and overall cancer risk was observed, suggesting that higher concentrations of lycopene may help lower cancer risk overall. Men with the highest levels of serum lycopene had a 45% lower risk of cancer than did men with the lowest levels of lycopene (risk ratio, 0.55; 95% confidence interval (CI), 0.34–0.89; P = .015). However, when the analysis was restricted to specific cancer types, an association was observed for other cancers (risk ratio, 0.43; 95% CI, 0.23–0.79; P = .007) but not prostate cancer.[24]

A 2004 meta-analysis of studies investigating tomato intake and prostate cancer risk found a small positive effect of tomato products on risk reduction. Among men who consumed high amounts of raw tomato products, the relative risk (RR) of prostate cancer was 0.89 (95% CI, 0.80–1.00), compared with men who ate the least amount of raw tomatoes. For men who consumed the most cooked tomato products, the RR was 0.81 (95% CI, 0.71–0.92).[25] A 2013 meta-analysis, including four of five cohort studies from the 2004 meta-analysis, two new meta-analyses and three case-control studies from the previous study plus eight new ones, reported less convincing evidence for risk reduction.[26] Among men who consumed high amounts of raw tomato products, the RR of prostate cancer was 0.81 (95% CI, 0.59–1.10), compared with men who ate the least amount of raw tomatoes. For men who consumed the most cooked tomatoes products, the RR was 0.85 (95% CI, 0.69–1.06). These authors concluded that tomato may play a modest role in the prevention of prostate cancer.

The National Cancer Institute's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial is an ongoing, prospective study that has been a source of subjects for investigations of an association between lycopene intake and prostate cancer risk. A 2006 study examined lycopene and tomato product intakes and prostate cancer risk among PLCO participants who had been followed up for an average of 4.2 years. Lycopene and tomato product intakes were assessed via Food Frequency Questionnaires. Overall, no association was found between dietary intake of lycopene or tomato products and the risk of prostate cancer. However, among men with a family history of prostate cancer, increased lycopene consumption was associated with decreased prostate cancer risk.[27] A follow-up study was conducted that examined serum lycopene and risk of prostate cancer in the same group of PLCO participants. The results suggest that there was no significant difference in serum lycopene concentrations between healthy participants and participants who developed prostate cancer.[28]

The Health Professionals Follow-up Study obtained dietary information and ascertained total and lethal prostate cancer cases from 1986 through January 31, 2010. Higher lycopene intake was inversely associated with total prostate cancer risk (hazard ratio [HR], 0.91; 95% CI, 0.84–1.00) and lethal prostate cancer risk (HR, 0.72; 95% CI, 0.56–0.94). A subset analysis was restricted to men who had at least one negative PSA test at the onset, to reduce the influence of PSA screening on the association. The inverse association became markedly stronger (HR, 0.47; 95% CI, 0.29–0.75 for lethal prostate cancer). Levels of tumor markers for angiogenesis, apoptosis, and cellular proliferation and differentiation were monitored. Three of the tumor angiogenesis markers were strongly associated with lycopene intake, so that men with higher intake had tumors that demonstrated less angiogenic potential.[29]

The variability in these epidemiological study results may be related to lycopene source; exposure misclassification; lack of a dose response; and confounding lifestyle factors, such as obesity, use of tobacco and alcohol, other dietary differences, varying standardization of quantities and compositions of lycopene, geographical location, and genetic risk factors. Given these caveats, results based on epidemiological evidence should be interpreted with caution.

Intervention studies

A number of clinical studies have been conducted investigating lycopene as a chemopreventive agent and as a potential treatment for prostate cancer.

Healthy males participated in a crossover design study that attempted to differentiate the effects of tomatoes from those of lycopene. After study entry, the participants consumed their usual diet for 1 week followed by a 2-week washout period on a lycopene-free diet. Next, they were randomly assigned to consume either yellow tomato paste (0 mg/day lycopene) (Group 1) or red tomato paste (16 mg/day lycopene) (Group 2) for 1 week as part of their regular diets, followed by a second 2-week washout period. Then, the participants in Group 1 crossed over to red tomato paste, and the participants in Group 2 crossed over to yellow tomato paste for 1 week as part of their regular diets, followed by a third 2-week washout period. Finally, the participants in Group 1 took a capsule of lycopene (16 mg/day) and the participants in Group 2 took a placebo daily for 1 week. Circulating lycopene levels increased only after consumption of red tomato paste and the lycopene capsules. Changes in serum PSA level, antioxidant status, and IGF-1 level were not modified by the consumption of tomato paste and lycopene. When prostate cancer cells were treated in vitro with sera collected from participants after red tomato paste consumption, IGF binding protein-3 (IGFBP-3) and the ratio of Bax to Bcl2 were up regulated, and cyclin-D1, p53, and Nrf-2 were down regulated compared with expression levels obtained using sera taken after the first washout period. Intermediate gene expression changes were observed using sera collected from participants after yellow tomato paste consumption. These findings suggest that lycopene may not be the only factor responsible for the protective effects of tomatoes.[30]

In another study, the effect of tomato sauce on apoptosis in benign prostate hyperplasia (BPH) tissue and carcinomas was examined. Patients who were scheduled for prostatectomy were given tomato sauce pasta entrees (30 mg/day of lycopene) to eat daily for 3 weeks before surgery. Patients scheduled for surgery who did not receive the tomato sauce pasta entrees served as control subjects. Those who consumed the tomato sauce pasta entrees exhibited significantly decreased serum PSA levels and increased apoptotic cell death in BPH tissue and carcinomas.[31]

In a third study, patients with high-grade prostate intraepithelial neoplasia (HGPIN) received 4 mg of lycopene twice a day or no lycopene supplementation for 2 years. A greater decrease in serum PSA levels was observed in those treated with lycopene supplements, compared with those who did not take the supplementation. During follow-up, adenocarcinomas were diagnosed more often in patients who had not received the supplements than in patients who had received lycopene (6/20 vs. 2/20). These findings suggest that lycopene may be effective in preventing HGPIN from progressing to prostate cancer.[32] In another study, men at high risk of prostate cancer (e.g., HGPIN) were randomly assigned to receive a daily multivitamin (that did not contain lycopene) or the same multivitamin and a lycopene supplement (30 mg/day) for 4 months. No statistically-significant difference was observed in serum PSA levels between the two treatment groups. These findings suggest that, although lycopene supplements may be safe to take for at least 4 months, they may not affect PSA levels.[33]

In another study, 32 men with HGPIN received a lycopene-enriched diet (20–25 mg/day lycopene from triple-concentrated tomato paste) before undergoing a repeat biopsy after 6 months. No overall clinical benefit was seen in decreasing the rate of progression to prostate cancer. Baseline PSA levels showed no significant change. Prostatic lycopene concentration was the only difference between those whose repeat biopsy showed HGPIN, prostatitis, or prostate cancer. Prostatic lycopene concentration below 1 ng/mg was associated with prostate cancer at the 6-month follow-up biopsy (P = .003).[34]

Other studies have examined the potential therapeutic effect of lycopene-containing products in patients with prostate cancer. The effects of lycopene supplementation on prostate tissue and prostate cancer biomarkers were investigated in patients with localized prostate cancer in a 2002 pilot study. Patients received lycopene supplements (30mg/day) or no intervention twice daily for 3 weeks prior to radical prostatectomy. Patients who received the lycopene supplements had smaller tumors and lower serum PSA levels than patients who did not receive the supplements. These results suggest that lycopene may be beneficial in prostate cancer treatment.[35] A 2006 study investigated whether lycopene supplements (10 mg/day) would affect PSA velocity in patients with localized prostate cancer over the course of 1 year of treatment. There was a statistically significant decrease in PSA velocity following lycopene treatment as well as a large, but not statistically significant, increase in PSA doubling time.[36]

In a phase II, randomized, placebo-controlled trial,[37] 45 men with clinically localized prostate cancer received either 15, 30, or 45 mg of lycopene or no supplement from time of biopsy to prostatectomy (30 days). Plasma lycopene increased from baseline to the end of treatment in all treatment groups, with the greatest increase observed in the 45 mg lycopene-supplemented arm. No toxicity was reported. Overall, men with prostate cancer had lower baseline levels of plasma lycopene, similar to levels observed in previous studies in men with prostate cancer. At the 30 mg lycopene dose level, a moderate decrease in mean free testosterone and a significant increase in mean plasma estradiol was observed (24.90 [+/−7.94] to 32.30 [+/−7.93]; P = .02). In addition, significant increase in serum sex hormone-binding globulin (SHBG) (39.31 [+/−16.04] to 45.67 [+/−19.83]; P = .022) and total estradiol (27.54 pmol/L [SD 7.82] to 37.64 pmol/L [SD12.65]; P = .006) was observed in the 45 mg/day lycopene-supplemented arm, with no significant change in serum testosterone. However, serum testosterone and SHBG levels in the control group remained unchanged. The mean difference between groups who received the lycopene supplementation demonstrated a lower percentage of cells expressing Ki-67, compared with the control group. Notably, 75% of subjects in the 30 mg lycopene-supplemented arm had a decrease in the percentage of cells expressing Ki-67, compared with the subjects in the control group, where 100% of the subjects observed an increase. These changes were not statistically significant, compared with the changes in the control arm for this sample size and duration of intervention. Although antioxidant properties of lycopene have been hypothesized to be primarily responsible for its beneficial effects, this study suggests that other mechanisms mediated by steroid hormones may also be involved.[37]

In one study, prostate cancer patients (N = 36) who had biochemical relapse following radiation therapy or surgery received lycopene supplements twice daily for 1 year. There were six cohorts in the study, each receiving a different dose of lycopene (15, 30, 45, 60, 90, or 120 mg/day). Serum PSA levels did not respond to lycopene treatment. Plasma lycopene levels rose and appeared to plateau by 3 months for all doses. The results indicate that, although lycopene may be safe and well tolerated, it did not alter serum PSA levels in biochemically relapsed prostate cancer patients.[38]

In a 2004 open-label study, patients with hormone-refractory prostate cancer (HRPC) (N = 20) received lycopene supplements daily (10 mg/day of lycopene) for 3 months. Of the study's participants, 50% had PSA levels that remained stable, 15% showed biochemical progression, 30% showed a partial response, and one patient (5% of the total sample) exhibited a complete response after treatment.[39] In a phase II study, HRPC patients took lycopene supplements daily (15 mg of lycopene/day) for 6 months. By the end of the study, serum PSA levels had almost doubled in 12 of the 17 patients, and 5 of 17 patients had achieved PSA stabilization. Although this was a small study without a control group, the results suggest that lycopene may not be beneficial for patients with advanced prostate cancer.[40]

In another study, 46 patients with androgen-independent prostate cancer consumed either tomato paste or tomato juice daily (both preparations provided 30 mg of lycopene/day) for at least 4 months. Only one patient in this study exhibited a decrease in PSA level, suggesting that lycopene may not be effective therapy for patients with androgen-independent prostate cancer. A number of participants experienced gastrointestinal side effects after eating the tomato paste or drinking the tomato juice.[41]

In one 2011 study that explored the effects of lycopene and fish oil supplements on gene expression, men with low-risk prostate cancer were randomly assigned to receive lycopene (30 mg of lycopene/day), fish oil (3 g of fish oil capsules/day), or a placebo daily for 90 days. Gene expression analysis showed no statistically significant differential expression of individual genes associated with the consumption of fish oil or lycopene supplements. However, pathway analysis revealed that an oxidative stress response pathway was significantly modulated following lycopene or fish oil supplement use compared with placebo (fish oil: P = .01, lycopene: P = .001).[42]

Current Clinical Trials

Check NCI’s list of cancer clinical trials for CAM clinical trials on lycopene for prostate cancer that are actively enrolling patients.

General information about clinical trials is also available from the NCI Web site.

Adverse Effects

Lycopene has been well tolerated in a number of clinical trials involving prostate cancer patients.[30,32,33,36,39] When adverse effects occurred, they tended to present as gastrointestinal symptoms[41] and, in one study, the symptoms resolved when lycopene was taken with meals.[40] Another study reported that one participant withdrew because of diarrhea.[38]

The FDA has accepted the determination by various companies that their lycopene-containing products meet the FDA’s requirements for the designation of Generally Recognized as Safe (GRAS).[43]

References
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  16. Zhang X, Wang Q, Neil B, et al.: Effect of lycopene on androgen receptor and prostate-specific antigen velocity. Chin Med J (Engl) 123 (16): 2231-6, 2010.  [PUBMED Abstract]

  17. Qiu X, Yuan Y, Vaishnav A, et al.: Effects of lycopene on protein expression in human primary prostatic epithelial cells. Cancer Prev Res (Phila) 6 (5): 419-27, 2013.  [PUBMED Abstract]

  18. Tang Y, Parmakhtiar B, Simoneau AR, et al.: Lycopene enhances docetaxel's effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels. Neoplasia 13 (2): 108-19, 2011.  [PUBMED Abstract]

  19. Konijeti R, Henning S, Moro A, et al.: Chemoprevention of prostate cancer with lycopene in the TRAMP model. Prostate 70 (14): 1547-54, 2010.  [PUBMED Abstract]

  20. Mossine VV, Chopra P, Mawhinney TP: Interaction of tomato lycopene and ketosamine against rat prostate tumorigenesis. Cancer Res 68 (11): 4384-91, 2008.  [PUBMED Abstract]

  21. Yang CM, Yen YT, Huang CS, et al.: Growth inhibitory efficacy of lycopene and β-carotene against androgen-independent prostate tumor cells xenografted in nude mice. Mol Nutr Food Res 55 (4): 606-12, 2011.  [PUBMED Abstract]

  22. Yang CM, Lu YL, Chen HY, et al.: Lycopene and the LXRα agonist T0901317 synergistically inhibit the proliferation of androgen-independent prostate cancer cells via the PPARγ-LXRα-ABCA1 pathway. J Nutr Biochem 23 (9): 1155-62, 2012.  [PUBMED Abstract]

  23. Kristal AR, Till C, Platz EA, et al.: Serum lycopene concentration and prostate cancer risk: results from the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 20 (4): 638-46, 2011.  [PUBMED Abstract]

  24. Karppi J, Kurl S, Nurmi T, et al.: Serum lycopene and the risk of cancer: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study. Ann Epidemiol 19 (7): 512-8, 2009.  [PUBMED Abstract]

  25. Etminan M, Takkouche B, Caamaño-Isorna F: The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev 13 (3): 340-5, 2004.  [PUBMED Abstract]

  26. Chen J, Song Y, Zhang L: Lycopene/tomato consumption and the risk of prostate cancer: a systematic review and meta-analysis of prospective studies. J Nutr Sci Vitaminol (Tokyo) 59 (3): 213-23, 2013.  [PUBMED Abstract]

  27. Kirsh VA, Mayne ST, Peters U, et al.: A prospective study of lycopene and tomato product intake and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 15 (1): 92-8, 2006.  [PUBMED Abstract]

  28. Peters U, Leitzmann MF, Chatterjee N, et al.: Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 16 (5): 962-8, 2007.  [PUBMED Abstract]

  29. Zu K, Mucci L, Rosner BA, et al.: Dietary lycopene, angiogenesis, and prostate cancer: a prospective study in the prostate-specific antigen era. J Natl Cancer Inst 106 (2): djt430, 2014.  [PUBMED Abstract]

  30. Talvas J, Caris-Veyrat C, Guy L, et al.: Differential effects of lycopene consumed in tomato paste and lycopene in the form of a purified extract on target genes of cancer prostatic cells. Am J Clin Nutr 91 (6): 1716-24, 2010.  [PUBMED Abstract]

  31. Kim HS, Bowen P, Chen L, et al.: Effects of tomato sauce consumption on apoptotic cell death in prostate benign hyperplasia and carcinoma. Nutr Cancer 47 (1): 40-7, 2003.  [PUBMED Abstract]

  32. Mohanty NK, Saxena S, Singh UP, et al.: Lycopene as a chemopreventive agent in the treatment of high-grade prostate intraepithelial neoplasia. Urol Oncol 23 (6): 383-5, 2005 Nov-Dec.  [PUBMED Abstract]

  33. Bunker CH, McDonald AC, Evans RW, et al.: A randomized trial of lycopene supplementation in Tobago men with high prostate cancer risk. Nutr Cancer 57 (2): 130-7, 2007.  [PUBMED Abstract]

  34. Mariani S, Lionetto L, Cavallari M, et al.: Low prostate concentration of lycopene is associated with development of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia. Int J Mol Sci 15 (1): 1433-40, 2014.  [PUBMED Abstract]

  35. Kucuk O, Sarkar FH, Djuric Z, et al.: Effects of lycopene supplementation in patients with localized prostate cancer. Exp Biol Med (Maywood) 227 (10): 881-5, 2002.  [PUBMED Abstract]

  36. Barber NJ, Zhang X, Zhu G, et al.: Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study. Prostate Cancer Prostatic Dis 9 (4): 407-13, 2006.  [PUBMED Abstract]

  37. Kumar NB, Besterman-Dahan K, Kang L, et al.: Results of a Randomized Clinical Trial of the Action of Several Doses of Lycopene in Localized Prostate Cancer: Administration Prior to Radical Prostatectomy. Clin Med Urol 1: 1-14, 2008.  [PUBMED Abstract]

  38. Clark PE, Hall MC, Borden LS Jr, et al.: Phase I-II prospective dose-escalating trial of lycopene in patients with biochemical relapse of prostate cancer after definitive local therapy. Urology 67 (6): 1257-61, 2006.  [PUBMED Abstract]

  39. Ansari MS, Gupta NP: Lycopene: a novel drug therapy in hormone refractory metastatic prostate cancer. Urol Oncol 22 (5): 415-20, 2004 Sep-Oct.  [PUBMED Abstract]

  40. Schwenke C, Ubrig B, Thürmann P, et al.: Lycopene for advanced hormone refractory prostate cancer: a prospective, open phase II pilot study. J Urol 181 (3): 1098-103, 2009.  [PUBMED Abstract]

  41. Jatoi A, Burch P, Hillman D, et al.: A tomato-based, lycopene-containing intervention for androgen-independent prostate cancer: results of a Phase II study from the North Central Cancer Treatment Group. Urology 69 (2): 289-94, 2007.  [PUBMED Abstract]

  42. Magbanua MJ, Roy R, Sosa EV, et al.: Gene expression and biological pathways in tissue of men with prostate cancer in a randomized clinical trial of lycopene and fish oil supplementation. PLoS One 6 (9): e24004, 2011.  [PUBMED Abstract]

  43. Generally Recognized as Safe (GRAS) Notice Inventory. Silver Spring, Md: Food and Drug Administration, 2011. Available online. Last accessed October 9, 2014. 

Modified Citrus Pectin



Overview

This section contains the following key information:

  • Citrus pectin is a complex polysaccharide found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature.

  • Preclinical research suggests that modified citrus pectin (MCP) may have effects on cancer growth and metastasis through multiple potential mechanisms.

  • Very limited clinical research has been done with a couple of citrus pectin-containing products. For prostate cancer patients, the results suggest some potential clinical benefits with relatively minor and infrequent adverse events.

General Information and History

Pectin is a complex polysaccharide contained in the primary cell walls of terrestrial plants. The word ‘pectin’ comes from the Greek word for congealed or curdled. Plant pectin is used in food processing as a gelling agent and also in the formulation of oral and topical medicines as a stabilizer and nonbiodegradable matrix to support controlled drug delivery.[1] Citrus pectin is found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature.[2] Modification results in shorter molecules that dissolve better in water and are more readily absorbed by the body than are complex, longer chain citrus pectins.[3] One of the molecular targets of MCP is galectin-3, a protein found on the surface and within mammalian cells that is involved in many cellular processes, including cell adhesion, cell activation and chemoattraction, cell growth and differentiation, the cell cycle, and apoptosis; MCP inhibits galectin-3 activity.[2]

Some research suggests that MCP may be protective against various types of cancer, including colon, lung, and prostate cancer. MCP may exert its anticancer effects by interfering with tumor cell metastasis or by inducing apoptosis.[4]

MCP was also shown to activate natural killer cells in leukemic cell cultures, suggesting it may be able to stimulate the immune system.[5]

Preclinical Studies/Animal Studies

In vitro studies

In a 2007 study, pectins were investigated for their anticancer properties. Prostate cancer cells were treated with three different pectins; citrus pectin (CP), Pectasol (PeS, a dietary supplement containing modified citrus pectin), and fractionated pectin powder (FPP). FPP induced apoptosis to a much greater degree than did CP and PeS. Further analysis revealed that treating prostate cancer cells with heated CP resulted in levels of apoptosis similar to those following treatment with FPP. This suggests that specific structural features of pectin may be responsible for its ability to induce apoptosis in prostate cancer cells.[4]

In a 2010 study, prostate cancer cells were treated with PeS or PectaSol-C, the only two MCPs previously used in human trials. The researchers postulated that, because it has a lower molecular weight, PectaSol-C may have better bioavailability than PeS. Both types of MCP were tested at a concentration of 1 mg/mL and both were effective in inhibiting cell growth and inducing apoptosis through inhibition of the MAPK/ERK signaling pathway and activation of the enzyme caspase-3.[6]

In another study, the role of galectin-3, a multifunctional endogenous lectin, in cisplatin -treated prostate cancer cells was examined. Prostate cancer cells that expressed galectin-3 were found to be resistant to the apoptotic effects of cisplatin. However, cells that did not express galectin-3 (via silencing RNA knockdown of galectin-3 expression or treatment with MCP) were susceptible to cisplatin-induced apoptosis. These findings suggest that galectin-3 expression may play a role in prostate cancer cell chemoresistance and that the efficacy of cisplatin treatment in prostate cancer may be improved by inhibiting galectin-3.[7]

Animal studies

Only a few studies have been reported on the effects of MCP in animals bearing implanted cancers and only one involving prostate cancer.[8,9] The prostate cancer study examined the effects of MCP on the metastasis of prostate cancer cells injected into rats. In the study, rats were given 0.0%, 0.01%, 0.1%, or 1.0% MCP (wt/vol) in their drinking water beginning 4 days after cancer cell injection. The analysis revealed that treatment with 0.1% and 1.0% MCP resulted in statistically significant reductions in lung metastases but did not affect primary tumor growth.[9]

Human Studies

Intervention studies

In a 2007 pilot study, patients with advanced solid tumors (various types of cancers were represented, including prostate cancer) received MCP (5 g MCP powder dissolved in water) 3 times a day for at least 8 weeks. Following treatment, improvements were reported in some measures of quality of life, including physical functioning, global health status, fatigue, pain, and insomnia. In addition, 22.5% of participants had stable disease after 8 weeks of MCP treatment, and 12.3% of participants had disease stabilization lasting more than 24 weeks.[3]

The effect of MCP on prostate-specific antigen (PSA) doubling time (PSADT) was investigated in a 2003 study. Prostate cancer patients with rising PSA levels received six PeS capsules 3 times a day (totaling 14.4 g of MCP powder daily) for 12 months. Following treatment, 7 of 10 patients had a statistically significant (P ≤ .05) increase in PSADT.[10]

Current Clinical Trials

Check NCI’s list of cancer clinical trials for CAM clinical trials on modified citrus pectin for prostate cancer that are actively enrolling patients.

General information about clinical trials is also available from the NCI Web site.

Adverse Effects

In one prospective pilot study, MCP was well tolerated by the majority of treated patients, with the most commonly reported side effects being pruritus, dyspepsia, and flatulence.[3] In another study, no serious side effects from MCP were reported, although three patients withdrew from the study due to abdominal cramps and diarrhea that improved once treatment was halted.[10]

References
  1. Mohnen D: Pectin structure and biosynthesis. Curr Opin Plant Biol 11 (3): 266-77, 2008.  [PUBMED Abstract]

  2. Glinsky VV, Raz A: Modified citrus pectin anti-metastatic properties: one bullet, multiple targets. Carbohydr Res 344 (14): 1788-91, 2009.  [PUBMED Abstract]

  3. Azemar M, Hildenbrand B, Haering B, et al.: Clinical benefit in patients with advanced solid tumors treated with modified citrus pectin: a prospective pilot study. Clin Med Oncol 1: 73-80, 2007. Available online. Last accessed October 9, 2014. 

  4. Jackson CL, Dreaden TM, Theobald LK, et al.: Pectin induces apoptosis in human prostate cancer cells: correlation of apoptotic function with pectin structure. Glycobiology 17 (8): 805-19, 2007.  [PUBMED Abstract]

  5. Ramachandran C, Wilk BJ, Hotchkiss A, et al.: Activation of human T-helper/inducer cell, T-cytotoxic cell, B-cell, and natural killer (NK)-cells and induction of natural killer cell activity against K562 chronic myeloid leukemia cells with modified citrus pectin. BMC Complement Altern Med 11: 59, 2011.  [PUBMED Abstract]

  6. Yan J, Katz A: PectaSol-C modified citrus pectin induces apoptosis and inhibition of proliferation in human and mouse androgen-dependent and- independent prostate cancer cells. Integr Cancer Ther 9 (2): 197-203, 2010.  [PUBMED Abstract]

  7. Wang Y, Nangia-Makker P, Balan V, et al.: Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment. Cell Death Dis 1: e101, 2010.  [PUBMED Abstract]

  8. Hayashi A, Gillen AC, Lott JR: Effects of daily oral administration of quercetin chalcone and modified citrus pectin on implanted colon-25 tumor growth in Balb-c mice. Altern Med Rev 5 (6): 546-52, 2000.  [PUBMED Abstract]

  9. Pienta KJ, Naik H, Akhtar A, et al.: Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst 87 (5): 348-53, 1995.  [PUBMED Abstract]

  10. Guess BW, Scholz MC, Strum SB, et al.: Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study. Prostate Cancer Prostatic Dis 6 (4): 301-4, 2003.  [PUBMED Abstract]

Pomegranate



Overview

This section contains the following key information:

  • The pomegranate (Punica granatum L.) is native to Asia and cultivated widely throughout world.

  • Various components of the pomegranate fruit contain bioactive compounds, including catechin phenolics, related flavonoids, and anthocyanins, some of which have antioxidant activity.

  • Pomegranate juice and extract, as well as some of their bioactive components, inhibit the proliferation of various prostate cancer cell lines in vitro and induce apoptotic cell death in a dose-dependent manner.

  • Cytochrome P450 enzyme inhibition and effects on insulin-like growth factor binding protein -3 (IGFBP-3) have been identified as being involved in the in vitro anticancer activity.

  • Studies in rodent models of prostate cancer have shown that ingestion of pomegranate juice can decrease the rate of development, growth, and spread of prostate cancer.

  • The only fully reported clinical trial of the use of pomegranate juice in men with prostate cancer showed that, on average, study participants who drank the juice had an increase in their prostate-specific antigen (PSA) doubling time.

  • No serious adverse effects have been reported in clinical trials of pomegranate juice administration (8 oz per day for up to 33 months).

  • A phase II study reported that pomegranate extract was associated with an increase of at least 6 month in PSA doubling time in both treatment arms (different doses), without adverse effects.

General Information and History

The pomegranate (Punica granatum L.) is a member of the Punicaceae family native to Asia (from Iran to northern India) and cultivated throughout the Mediterranean, Southeast Asia, East Indies, Africa, and the United States.[1] The history of the pomegranate goes back centuries—the fruit is considered sacred by many religions and has been used for medicinal purposes since ancient times.[2] The fruit is comprised of peel (pericarp), seeds, and aril (outer layer surrounding the seeds). The peel makes up 50% of the fruit and contains a number of bioactive compounds, including phenolics, flavonoids, and ellagitannins, and minerals such as potassium, magnesium, and sodium. Arils are mainly composed of water and also contain phenolics and flavonoids. Anthocyanins, which are flavonoid present in arils, are responsible for the fruit's and its juice’s red color.[3] The majority of antioxidant activity comes from ellagitannins.[4]

Research studies suggest that pomegranates have beneficial effects on a number of health conditions, including cardiovascular disease,[5] and may also have positive effects on oral or dental health.[6]

Preclinical Studies/Animal Studies

Research studies in the laboratory have examined the effects of pomegranate on many prostate cancer cell lines and in rodent models of the disease.

In vitro studies

Ellagitannins (the main polyphenols in pomegranate juice) are hydrolyzed to ellagic acid, and then to urolithin A (UA) derivatives. According to a tissue distribution experiment in wild-type mice, the prostate gland rapidly takes up high concentrations of UA after oral or intraperitoneal administration (0.3mg/mouse/dose). Ellagic acid was detected in the prostate following intraperitoneal, but not oral, administration of pomegranate extract (0.8mg/mouse/dose).[7]

Treating human prostate cancer cells with individual components of the pomegranate fruit has been shown to inhibit cell growth.[8-11] In one study, dihydrotestosterone -stimulated LNCaP cells were treated with 13 pomegranate compounds at various concentrations (0-100 µM).[9] Four of the 13 compounds, epigallocatechin gallate (EGCG), delphinidin chloride, kaempferol, and punicic acid, exhibited an ability to inhibit cell growth in a dose-dependent manner. Treating cells with EGCG, kaempferol, and punicic acid further resulted in apoptosis, with punicic acid (the primary constituent of pomegranate seeds) being the strongest inducer of apoptosis. Additionally, findings from this study suggest that punicic acid may activate apoptosis by a caspase-dependent pathway.[9]

Pomegranate extracts have also been shown to inhibit the proliferation of human prostate cancer cells in vitro.[10,12,13] In one study, three prostate cancer cell lines (LNCaP, LNCaP-AR, and DU-145) were treated with pomegranate polyphenols [punicalagin (PA) or ellagic acid (EA)], a pomegranate extract (POMx, which contains EA and PA), or pomegranate juice (PJ, which contains PA, EA, and anthocyanins) in concentrations ranging from 3.125 to 50 µg/mL (standardized to PA content). All four treatments resulted in statistically significant increases in apoptosis and dose-dependent decreases in cell proliferation in the three cell lines. However, PJ and POMx were stronger inhibitors of cell growth than were PA and EA. In this study, the effects of PA, EA, POMx, and PJ on the expression of androgen -synthesizing enzyme genes and the androgen receptor were also measured. Although statistically significant decreases in gene expression occurred in LNCaP cells following treatment with POMx and in DU-145 cells following treatment with EA and POMx, significant decreases in gene expression and androgen receptor occurred in LNCaP-AR cells following all of the treatments.[10] In another study, treating PC3 cells (human prostate cancer cells with a high metastatic potential) with POMx (10-100 µg/mL) resulted in cell growth inhibition and apoptosis, both in a dose-dependent manner. Treatment of CWR22Rv1 cells (prostate cancer cells that express the androgen receptor and secrete PSA) with POMx (10-100 µg/mL concentrations of pomegranate fruit extract) led to the inhibition of cell growth, a dose-dependent decrease in androgen receptor protein expression, and dose-dependent reductions in PSA protein levels.[13]

The enzyme cytochrome P450 (CYP1B1) has been implicated in cancer development and progression. As a result, CYP1B1 inhibitors may be effective anti-carcinogenic targets. In a study reported in 2009, the effects of pomegranate metabolites on CYP1B1 activation and expression in CWR22Rv1 prostate cancer cells were examined. In this study, urolithins A and B inhibited CYP1B1 expression and activity.[14]

In addition, the insulin-like growth factor (IGF) system has been implicated in prostate cancer. A study reported in 2010 examined the effects of a POMx on the IGF system. Treating LAPC4 prostate cancer cells with POMx (10 µg/mL concentration of pomegranate extract prepared from skin and arils minus seeds) resulted in cell growth inhibition and apoptosis, but treating the cells with both reagents led to larger effects on growth inhibition and apoptosis. However, these substances may have induced apoptosis by different mechanisms. Other findings suggested that POMx treatment reduced mTOR phosphorylation at Ser2448 and Ser2481, whereas IGFBP-3 increased phosphorylation at those sites. In addition, CWR22Rv1 cells treated with POMx (1 and 10 µg/mL) exhibited a dose-dependent reduction in IGF1 mRNA levels, but treatment with IGFBP-3 or IGF-1 did not alter levels of IGF1; these results suggest that one way POMx decreases prostate cancer cell survival is by inhibiting IGF1 expression.[12]

In a study reported in 2011, human hormone -independent prostate cancer cells (DU145 and PC3 cell lines) were treated with 1% or 5% PJ for times ranging from 12 to 72 hours. The results showed that treatment with PJ increased adhesion and decreased the migration of prostate cancer cells. Molecular analyses revealed that PJ increased the expression of cell-adhesion related genes and inhibited the expression of genes involved in cytoskeletal function and cellular migration. These findings suggest that PJ may be beneficial in slowing down or preventing cancer cell metastasis.[15]

Animal studies

The effects of pomegranate on prostate cancer have been examined using a number of rodent models of the disease. In one study, athymic nude mice were injected with tumor-forming cells. Following inoculation, animals were randomly assigned to receive normal drinking water or PJ (0.1% or 0.2% POMx in drinking water, which resulted in an intake corresponding to 250 or 500 mL of PJ per day for an average adult human). Small, solid tumors appeared earlier in mice drinking normal water only than in mice drinking PJ (8 days vs. 11-14 days). Moreover, tumor growth rates were significantly reduced in mice drinking PJ compared with mice drinking normal water only. Animals drinking PJ also exhibited significant reductions in serum PSA levels compared with animals drinking normal water only.[13] In other studies, treatment with a POMx resulted in decreased tumor volumes in SCID mice that had been injected with prostate cancer cells.[7,16]

Similarly, when nude mice were injected with pomegranate seed oil (2 µg/g body weight), pomegranate pericarp (peel) polyphenols (2 µg/g body weight), or saline 5 to 10 minutes prior to being implanted with solid prostate cancer tumors, mice injected with the pomegranate extracts had significantly smaller tumor volumes compared with the mice injected with saline (P < .001).[8]

In another study, which was reported in 2011, 6-week-old transgenic adenocarcinoma of the mouse prostate (TRAMP) mice received normal drinking water or PJ (0.1% or 0.2% POMx in drinking water) for 28 weeks. The results showed that 100% of the mice that received water only developed tumors by 20 weeks of age, whereas just 30% and 20% of the mice that received 0.1% and 0.2% PJ, respectively, developed tumors. By 34 weeks of age, 90% of the water-fed mice exhibited metastases to distant organs whereas only 20% of the mice that received pomegranate juice showed metastasis. The PJ-supplemented mice exhibited significantly increased life spans compared to the water-fed mice.[17]

Human Studies

In a study reported in 2006, researchers observed the effects of PJ on PSA values in prostate cancer patients (N = 48) who had rising PSA levels following treatment with surgery or radiation therapy. The study participants drank 8 ounces of PJ daily (570 mg/day total polyphenol gallic acid equivalents) for up to 33 months. Drinking PJ was associated with statistically significant increases in PSA doubling time (PSADT). After 33 months of follow-up, the median PSADT increased from 11.5 months to 28.7 months (P < .001). In addition, LNCaP cells were treated in vitro with the subjects’ serum before and after the PJ intervention. Results of the in vitro experiments showed a decrease in cell growth and an increase in apoptosis following PJ treatment.[18]

A phase II study evaluated 1-g and 3-g doses of pomegranate extract in 104 men with rising PSA values following initial therapy for localized prostate cancer.[19] The study reported that pomegranate extract was associated with an increase of at least 6 months in PSA doubling time in both treatment arms, without adverse effects.

Current Clinical Trials

Check NCI’s list of cancer clinical trials for CAM clinical trials on pomegranate-extract pill for prostate cancer, pomegranate juice for prostate cancer, and pomegranate liquid extract for prostate cancer that are actively enrolling patients.

General information about clinical trials is also available from the NCI Web site.

Adverse Effects

In a study of prostate cancer patients reported in 2006, the PJ intervention was well tolerated and no serious adverse effects were observed.[18]

In a pilot study reported in 2007, the safety of PJ in patients with erectile dysfunction was examined. No serious adverse effects were observed during this study, and no participant dropped out due to adverse side effects. In the analysis of the results, no statistical comparisons were made of the adverse side effects observed in the intervention arm and the placebo arm.[20]

References
  1. Jurenka JS: Therapeutic applications of pomegranate (Punica granatum L.): a review. Altern Med Rev 13 (2): 128-44, 2008.  [PUBMED Abstract]

  2. Langley P: Why a pomegranate? BMJ 321 (7269): 1153-4, 2000.  [PUBMED Abstract]

  3. Viuda-Martos M, Fernandez-Lopez J, Perez-Alvarez JA: Pomegranate and its many functional components as related to human health: a review. Compr Rev Food Sci Food Saf 9 (6): 635-54, 2010. Available online. Last accessed October 9, 2014. 

  4. Basu A, Penugonda K: Pomegranate juice: a heart-healthy fruit juice. Nutr Rev 67 (1): 49-56, 2009.  [PUBMED Abstract]

  5. Aviram M, Rosenblat M, Gaitini D, et al.: Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr 23 (3): 423-33, 2004.  [PUBMED Abstract]

  6. Menezes SM, Cordeiro LN, Viana GS: Punica granatum (pomegranate) extract is active against dental plaque. J Herb Pharmacother 6 (2): 79-92, 2006.  [PUBMED Abstract]

  7. Seeram NP, Aronson WJ, Zhang Y, et al.: Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland. J Agric Food Chem 55 (19): 7732-7, 2007.  [PUBMED Abstract]

  8. Albrecht M, Jiang W, Kumi-Diaka J, et al.: Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. J Med Food 7 (3): 274-83, 2004.  [PUBMED Abstract]

  9. Gasmi J, Sanderson JT: Growth inhibitory, antiandrogenic, and pro-apoptotic effects of punicic acid in LNCaP human prostate cancer cells. J Agric Food Chem 58 (23): 12149-56, 2010.  [PUBMED Abstract]

  10. Hong MY, Seeram NP, Heber D: Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor. J Nutr Biochem 19 (12): 848-55, 2008.  [PUBMED Abstract]

  11. Lansky EP, Jiang W, Mo H, et al.: Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Invest New Drugs 23 (1): 11-20, 2005.  [PUBMED Abstract]

  12. Koyama S, Cobb LJ, Mehta HH, et al.: Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF-IGFBP axis. Growth Horm IGF Res 20 (1): 55-62, 2010.  [PUBMED Abstract]

  13. Malik A, Afaq F, Sarfaraz S, et al.: Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci U S A 102 (41): 14813-8, 2005.  [PUBMED Abstract]

  14. Kasimsetty SG, Bialonska D, Reddy MK, et al.: Effects of pomegranate chemical constituents/intestinal microbial metabolites on CYP1B1 in 22Rv1 prostate cancer cells. J Agric Food Chem 57 (22): 10636-44, 2009.  [PUBMED Abstract]

  15. Wang L, Alcon A, Yuan H, et al.: Cellular and molecular mechanisms of pomegranate juice-induced anti-metastatic effect on prostate cancer cells. Integr Biol (Camb) 3 (7): 742-54, 2011.  [PUBMED Abstract]

  16. Sartippour MR, Seeram NP, Rao JY, et al.: Ellagitannin-rich pomegranate extract inhibits angiogenesis in prostate cancer in vitro and in vivo. Int J Oncol 32 (2): 475-80, 2008.  [PUBMED Abstract]

  17. Adhami VM, Siddiqui IA, Syed DN, et al.: Oral infusion of pomegranate fruit extract inhibits prostate carcinogenesis in the TRAMP model. Carcinogenesis 33 (3): 644-51, 2012.  [PUBMED Abstract]

  18. Pantuck AJ, Leppert JT, Zomorodian N, et al.: Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res 12 (13): 4018-26, 2006.  [PUBMED Abstract]

  19. Paller CJ, Ye X, Wozniak PJ, et al.: A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis 16 (1): 50-5, 2013.  [PUBMED Abstract]

  20. Forest CP, Padma-Nathan H, Liker HR: Efficacy and safety of pomegranate juice on improvement of erectile dysfunction in male patients with mild to moderate erectile dysfunction: a randomized, placebo-controlled, double-blind, crossover study. Int J Impot Res 19 (6): 564-7, 2007 Nov-Dec.  [PUBMED Abstract]

Selenium



Overview

This section contains the following key information:

  • Selenium is an essential trace mineral involved in a number of biological processes, including kinase regulation, gene expression, and immune function.

  • Animal and epidemiological studies have suggested there may be an inverse relationship between selenium supplementation and cancer risk.

  • The results of epidemiologic studies suggest some complexity in the association between blood levels of selenium and the risk of developing prostate cancer.

  • The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large multicenter clinical trial, was initiated to examine the effects of selenium and/or vitamin E on the development of prostate cancer.

  • Initial results of SELECT, published in 2009, showed no statistically significant difference in the rate of prostate cancer in men who were randomly assigned to receive the selenium supplements.

  • In 2011, updated results from SELECT showed no significant effects of selenium supplementation on risk, but men who took vitamin E alone had a 17% increase in prostate cancer risk compared with men who took placebo.

  • In 2014, an analysis of SELECT results showed that men who had high selenium status at baseline and who were randomly assigned to receive selenium supplementation had an increased risk of high-grade prostate cancer.

General Information and History

Selenium is an essential trace mineral involved in a number of biological processes, including enzyme regulation, gene expression, and immune function. Selenium was discovered in 1818 and named after the Greek goddess of the moon, Selene.[1] A number of selenoproteins have been identified in humans, including selenoprotein P (SEPP), which is the main selenium carrier in the body and is important for selenium homeostasis.

Food sources of selenium include meat, vegetables, and nuts. The selenium content of the soil where food is raised determines the amount of selenium found in plants and animals. For adults, the recommended daily allowance for selenium is 55 µg /d.[2] Most dietary selenium occurs as selenocysteine or selenomethionine.[1] Selenium accumulates in the thyroid gland, liver, pancreas, pituitary gland, and renal medulla.[3]

Selenium is a component of the enzyme glutathione peroxidase, an enzyme that functions as an antioxidant.[4] However, at high concentrations, selenium may function as a pro-oxidant.[2]

Selenium is implicated in a number of disease states. Selenium deficiency may result in Keshan disease, a form of childhood cardiomyopathy, and Kaskin-Beck disease, a bone disorder.[5] Some clinical trials have suggested that high levels of selenium may be associated with diabetes [6] and high cholesterol.[2]

Selenium may also play a role in cancer. Animal and epidemiological studies have suggested there may be an inverse relationship between selenium supplementation and cancer risk.[7] The Nutritional Prevention of Cancer Trial (NPC) was a randomized, placebo-controlled study designed to test the hypothesis that higher selenium levels were associated with lower incidence of skin cancer. The results indicated that selenium supplementation did not affect risk of skin cancer, although incidences of lung, colorectal, and prostate cancer were significantly reduced.[8]

There is evidence that selenoproteins may be associated with carcinogenesis. For example, reduced expression of glutathione peroxidase 3 and selenoprotein P have been observed in some tumors, while increased expression of glutathione peroxidase 2 occurs in colorectal and lung tumors.[7]

Preclinical/Animal Studies

In vitro studies

Different selenium-containing compounds have variable effects on prostate cancer cells as well as normal cells and tissues. Both naturally occurring and synthetic organic forms of selenium have been shown to decrease the growth and function of prostate cancer cells.[9] In a 2011 study, prostate cancer cells were treated with various forms of selenium; selenite and methylseleninic acid (MeSeA) had the greatest cytotoxic effects.[10]

Studies have suggested that selenium nanoparticles may be less toxic to normal tissues than are other selenium compounds. One study investigated the effects of selenium nanoparticles on prostate cancer cells. The treated cells had decreased activity of the androgen receptor, which led to apoptosis and growth inhibition.[11]

Sodium selenite

In a 2010 study, prostate cancer cells treated with sodium selenite (a natural form of selenium) exhibited increased levels of p53 (a tumor suppressor). Findings also revealed that p53 may play a key role in selenium-induced apoptosis.[12]

In another study, the prostate cancer cell line LNCaP was modified to separately overexpress each of four antioxidant enzymes. Cells from the modified cell line were then treated with sodium selenite. The cells overexpressing manganese superoxide dismutase (MnSOD) were the only ones able to suppress selenite-induced apoptosis. These findings suggest that superoxide production in mitochondria may be important in selenium-induced apoptosis occurring in prostate cancer cells and that levels of MnSOD in cancer cells may determine how effective selenium is in inhibiting those cells.[13]

One study treated prostate cancer cells and benign prostatic hyperplasia (BPH) cells with sodium selenite. Growth of LNCaP cells was stimulated by noncytotoxic, low concentrations of sodium selenite; while growth inhibition occurred in PC-3 cells at these concentrations—prompting the authors to suggest that selenium may be beneficial in advanced prostate cancer—selenium supplementation may have adverse effects in hormone-sensitive prostate cancer.[14] However, the relevance of these findings to the clinical setting is unclear. These experiments used selenium concentrations of 1 to 10 µg/mL, whereas the average U.S. adult male serum selenium concentrations are about 0.125 µg/mL,[15] and prostate tissue concentrations are about 1.5 µg/g.[16]

Animal studies

A 2012 study investigated whether various forms of selenium (i.e., SeMet and Se-yeast) differentially affect biomarkers in the prostate. Elderly dogs received nutritionally adequate or supranutritional levels of selenium in the form of SeMet or Se-yeast. Both types of selenium supplementation increased selenium levels in toenails and prostate to a similar degree. The different forms of selenium supplementation showed no significant differences in DNA damage, proliferation, or apoptosis in the prostate.[17]

At least one study has compared these three forms of selenium in athymic nude mice injected with human prostate cancer cells and found that MSeA was more effective in inhibiting tumor growth than was SeMet or selenite.[18] Another study investigated the effect of age on selenium chemoprevention in mice. Mice were fed selenium-depleted or selenium-containing (at nutritional or supranutritional levels) diets for 6 months or 4 weeks and were then injected with PC-3 prostate cancer cells. Adult mice that were fed selenium-containing diets exhibited fewer tumors than did adult mice fed selenium-depleted diets. In adult mice, selenium-depleted diets resulted in tumors with more necrosis and inflammation compared to selenium-containing diets. However, in young mice, tumor development and histopathology were not affected by dietary selenium.[19]

The effects of MSeA and methylselenocysteine (MSeC) have also been explored in a transgenic model of in situ murine prostate cancer development, the TRAMP mouse.[20] Treatment with MSeA and MSeC resulted in slower progression of prostatic intraepithelial neoplasia (PIN) lesions, decreased cell proliferation, and increased apoptosis compared to treatment with water. MSeA treatment also increased survival time of TRAMP mice. TRAMP mice that received MSeA treatment starting at age 10 weeks exhibited less aggressive prostate cancer than did mice that started treatment at 16 weeks, suggesting early intervention with MSeA may be more effective than later treatment. The same research group later investigated some of the cellular mechanisms responsible for the different effects of MSeA and MSeC. MSeA and MSeC were shown to affect proteins involved in different cellular pathways. MSeA mainly affected proteins related to prostate differentiation, androgen receptor signaling, protein folding, and endoplasmic reticulum-stress responses, whereas MSeC affected enzymes involved in phase II detoxification or cytoprotection.[21] Another study suggests that MSeA may inhibit cell growth and increase apoptosis by inactivating PKC isoenzymes.[22]

Human Studies

Epidemiological Studies

The results of epidemiological studies suggest some complexity in the association between the blood levels of selenium and the risk of acquiring prostate cancer. As part of the EPIC-Heidelberg study, men completed dietary questionnaires, had blood samples taken, and were monitored every 2 to 3 years for up to 10 years. The findings revealed a significantly decreased risk of prostate cancer for individuals with higher blood selenium concentrations.[23] In another prospective pilot study, prostate cancer patients had significantly lower whole blood selenium levels than did healthy males.[24] However, in a 2009 study of prostate cancer patients, men with higher plasma selenium levels were at greater risk of being diagnosed with aggressive prostate cancer.[25]

Various molecular pathways have been explored to better understand the association between blood selenium levels and the development of prostate cancer. In the EPIC-Heidelberg study, polymorphisms in the selenium-containing enzymes GPX1 and SEP15 genes were found to be associated with prostate cancer risk.[23] Another study that used DNA samples obtained from the EPIC-Heidelberg study suggested that prostate cancer risk may be associated with single nucleotide polymorphisms (SNPs) in thioredoxin reductase and selenoprotein K genes along with selenium status.[26] A 2012 study investigated associations between variants in selenoenzyme genes and risk of prostate cancer and prostate cancer–specific mortality. Among SNPs analyzed, only GPX1 rs3448 was related to overall prostate cancer risk.[27]

A retrospective analysis of prostate cancer patients and healthy controls showed an association between aggressive prostate cancer and decreased selenium and SEPP status.[28] In the Physicians' Health Study, links between SNPs in the selenoprotein P gene (SEPP1) and prostate cancer risk and survival were examined. Two SNPs were significantly associated with prostate cancer incidence: rs11959466 was associated with increased risk, and rs13168440 was associated with decreased risk. Tumor SEPP1 mRNA expression levels were lower in men with lethal prostate cancer than in men with nonlethal prostate cancer.[29] In one study, the direction of the association between blood selenium levels and advanced prostate cancer incidence differed according to which of two polymorphisms of the gene encoding the enzyme manganese superoxide dismutase (SOD2) a patient had. For men with the AA genotype, higher selenium levels were associated with a reduced risk of presenting with aggressive disease, whereas the opposite was seen among men with a V allele.[25]

Intervention Studies

Sixty adult males were randomly assigned to receive either a daily placebo or 200 µg of selenium glycinate supplements for 6 weeks. Blood samples were collected at the start and the end of the study. Compared to the placebo group, men who received selenium supplements exhibited significantly increased activity of two blood selenium enzymes and significantly decreased levels of prostate-specific antigen (PSA) at the end of the study.[30]

A meta-analysis published in 2012 reviewed human studies that investigated links between selenium intake, selenium status, and prostate cancer risk. The results suggested an association between decreased prostate cancer risk and a narrow range of selenium status (plasma selenium concentrations up to 170 ng/mL and toenail selenium concentrations between 0.85 and 0.94 µg/g).[31]

In another study, prostate cancer patients were randomly assigned to receive either combination silymarin (570 mg) and selenomethionine (240 µg) supplement or placebo daily for 6 months following radical prostatectomy. While there was no change in PSA levels between the groups after 6 months, the participants receiving supplements reported improved quality of life and showed decreases in LDL and total cholesterol.[32]

In one study, 140 prostate cancer patients undergoing active surveillance were randomly assigned to receive low-dose selenium (200 µg/d), high-dose selenium (800 µg/d), or placebo daily for up to 5 years. Selenium was given in the form of selenized yeast. Men receiving the high-dose selenium, and who had the highest baseline plasma selenium levels, had a higher PSA velocity than did men in the placebo group. There was not a significant effect of selenium supplements on PSA velocity in men who had lower baseline levels of selenium.[33]

In 2013, results of a phase 3 randomized, placebo-controlled trial investigating the effect of selenium supplementation on prostate cancer incidence in men at high risk for the disease were reported. Subjects (N = 699) were randomly assigned to receive either daily placebo or one of two doses of high-selenium yeast (200 µg/d or 400 µg/d). They were monitored every 6 months, up to 5 years. Compared with placebo, selenium supplementation had no effect on prostate cancer incidence or PSA velocity.[34] In an earlier study, men with HGPIN were randomly assigned to receive either placebo or 200 µg of selenium daily for 3 years or until prostate cancer diagnosis. The results suggested that selenium supplementation had no effect on prostate cancer risk.[35]

The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

On the basis of findings of from earlier studies,[8,36] the SELECT, a large multicenter clinical trial, was initiated by the National Institutes of Health in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer. SELECT was a phase III, randomized, double-blind, placebo-controlled, population-based trial.[37] More than 35,000 men, aged 50 years or older, from more than 400 study sites in the United States, Canada, and Puerto Rico were randomly assigned to receive vitamin E (alpha-tocopherol acetate, 400 IU daily) and a placebo, selenium (L-selenomethionine, 200 µg daily) and a placebo, vitamin E and selenium, or two placebos daily for 7 to 12 years. The primary endpoint of the clinical trial was incidence of prostate cancer.[37]

Initial results of SELECT were published in 2009. There were no statistically significant differences in rates of prostate cancer in the four groups. In the vitamin E–alone group, there was a nonsignificant increase in rates of prostate cancer (P = .06); in the selenium–alone group, there was a nonsignificant increase in incidence of diabetes mellitus (P = .16). On the basis of those findings, the data and safety monitoring committee recommended that participants stop taking the study supplements.[38]

Updated results were published in 2011. When compared with the placebo group, the rate of prostate cancer detection was significantly greater in the vitamin E–alone group (P = .008) and represented a 17% increase in prostate cancer risk. There was also greater incidence of prostate cancer in men who had taken selenium than in men who took placebo, but those differences were not statistically significant.[39]

A number of explanations have been suggested, including the dose and form of vitamin E that was used in the trial as well as the specific form of selenium chosen for the study. L-selenomethionine was used in SELECT, while selenite and selenized yeast had been used in previous studies. SELECT researchers chose selenomethionine because it was the major component of selenized yeast and because selenite was not absorbed well by the body, resulting in lower selenium stores.[40] In addition, there were concerns over product consistency with high-selenium yeast.[41] However, selenomethionine is involved in general protein synthesis and can have numerous metabolites such as methylselenol, which may have antitumor properties.[42,43]

Toenail selenium concentrations were examined in two-case cohort subset studies of SELECT participants. Total selenium concentration in the absence of supplementation was not associated with prostate cancer risk. Selenium supplementation in SELECT had no effect on prostate cancer risk among men with low selenium status at baseline but increased the risk of high-grade prostate cancer in men with higher baseline selenium status by 91% (P = .007). The authors concluded that men should avoid selenium supplementation at doses exceeding recommended dietary intakes.[44]

Current Clinical Trials

Check NCI’s list of cancer clinical trials for CAM clinical trials on selenium that are actively enrolling patients.

General information about clinical trials is also available from the NCI Web site.

Adverse Effects

Selenium supplementation was well tolerated in many clinical trials. In two published trials, there were no differences reported in adverse effects between placebo or treatment groups.[33,34] However, in SELECT, selenium supplementation was associated with a nonsignificant increase in incidence of diabetes mellitus (P = .08).[38]

References
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  2. Tanguy S, Grauzam S, de Leiris J, et al.: Impact of dietary selenium intake on cardiac health: experimental approaches and human studies. Mol Nutr Food Res 56 (7): 1106-21, 2012.  [PUBMED Abstract]

  3. Mordan-McCombs S, Brown T, Zinser G, et al.: Dietary calcium does not affect prostate tumor progression in LPB-Tag transgenic mice. J Steroid Biochem Mol Biol 103 (3-5): 747-51, 2007.  [PUBMED Abstract]

  4. Bodnar M, Konieczka P, Namiesnik J: The properties, functions, and use of selenium compounds in living organisms. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 30 (3): 225-52, 2012.  [PUBMED Abstract]

  5. Sunde RA: Selenium. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 711-8. 

  6. Boosalis MG: The role of selenium in chronic disease. Nutr Clin Pract 23 (2): 152-60, 2008 Apr-May.  [PUBMED Abstract]

  7. Davis CD, Tsuji PA, Milner JA: Selenoproteins and cancer prevention. Annu Rev Nutr 32: 73-95, 2012.  [PUBMED Abstract]

  8. Clark LC, Combs GF Jr, Turnbull BW, et al.: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276 (24): 1957-63, 1996.  [PUBMED Abstract]

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  11. Kong L, Yuan Q, Zhu H, et al.: The suppression of prostate LNCaP cancer cells growth by Selenium nanoparticles through Akt/Mdm2/AR controlled apoptosis. Biomaterials 32 (27): 6515-22, 2011.  [PUBMED Abstract]

  12. Sarveswaran S, Liroff J, Zhou Z, et al.: Selenite triggers rapid transcriptional activation of p53, and p53-mediated apoptosis in prostate cancer cells: Implication for the treatment of early-stage prostate cancer. Int J Oncol 36 (6): 1419-28, 2010.  [PUBMED Abstract]

  13. Xiang N, Zhao R, Zhong W: Sodium selenite induces apoptosis by generation of superoxide via the mitochondrial-dependent pathway in human prostate cancer cells. Cancer Chemother Pharmacol 63 (2): 351-62, 2009.  [PUBMED Abstract]

  14. Kandaş NO, Randolph C, Bosland MC: Differential effects of selenium on benign and malignant prostate epithelial cells: stimulation of LNCaP cell growth by noncytotoxic, low selenite concentrations. Nutr Cancer 61 (2): 251-64, 2009.  [PUBMED Abstract]

  15. Niskar AS, Paschal DC, Kieszak SM, et al.: Serum selenium levels in the US population: Third National Health and Nutrition Examination Survey, 1988-1994. Biol Trace Elem Res 91 (1): 1-10, 2003.  [PUBMED Abstract]

  16. Takata Y, Morris JS, King IB, et al.: Correlation between selenium concentrations and glutathione peroxidase activity in serum and human prostate tissue. Prostate 69 (15): 1635-42, 2009.  [PUBMED Abstract]

  17. Waters DJ, Shen S, Kengeri SS, et al.: Prostatic response to supranutritional selenium supplementation: comparison of the target tissue potency of selenomethionine vs. selenium-yeast on markers of prostatic homeostasis. Nutrients 4 (11): 1650-63, 2012.  [PUBMED Abstract]

  18. Li GX, Lee HJ, Wang Z, et al.: Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite. Carcinogenesis 29 (5): 1005-12, 2008.  [PUBMED Abstract]

  19. Holmstrom A, Wu RT, Zeng H, et al.: Nutritional and supranutritional levels of selenate differentially suppress prostate tumor growth in adult but not young nude mice. J Nutr Biochem 23 (9): 1086-91, 2012.  [PUBMED Abstract]

  20. Wang L, Bonorden MJ, Li GX, et al.: Methyl-selenium compounds inhibit prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit. Cancer Prev Res (Phila) 2 (5): 484-95, 2009.  [PUBMED Abstract]

  21. Zhang J, Wang L, Anderson LB, et al.: Proteomic profiling of potential molecular targets of methyl-selenium compounds in the transgenic adenocarcinoma of mouse prostate model. Cancer Prev Res (Phila) 3 (8): 994-1006, 2010.  [PUBMED Abstract]

  22. Gundimeda U, Schiffman JE, Chhabra D, et al.: Locally generated methylseleninic acid induces specific inactivation of protein kinase C isoenzymes: relevance to selenium-induced apoptosis in prostate cancer cells. J Biol Chem 283 (50): 34519-31, 2008.  [PUBMED Abstract]

  23. Steinbrecher A, Méplan C, Hesketh J, et al.: Effects of selenium status and polymorphisms in selenoprotein genes on prostate cancer risk in a prospective study of European men. Cancer Epidemiol Biomarkers Prev 19 (11): 2958-68, 2010.  [PUBMED Abstract]

  24. Muecke R, Klotz T, Giedl J, et al.: Whole blood selenium levels (WBSL) in patients with prostate cancer (PC), benign prostatic hyperplasia (BPH) and healthy male inhabitants (HMI) and prostatic tissue selenium levels (PTSL) in patients with PC and BPH. Acta Oncol 48 (3): 452-6, 2009.  [PUBMED Abstract]

  25. Chan JM, Oh WK, Xie W, et al.: Plasma selenium, manganese superoxide dismutase, and intermediate- or high-risk prostate cancer. J Clin Oncol 27 (22): 3577-83, 2009.  [PUBMED Abstract]

  26. Méplan C, Rohrmann S, Steinbrecher A, et al.: Polymorphisms in thioredoxin reductase and selenoprotein K genes and selenium status modulate risk of prostate cancer. PLoS One 7 (11): e48709, 2012.  [PUBMED Abstract]

  27. Geybels MS, Hutter CM, Kwon EM, et al.: Variation in selenoenzyme genes and prostate cancer risk and survival. Prostate 73 (7): 734-42, 2013.  [PUBMED Abstract]

  28. Meyer HA, Hollenbach B, Stephan C, et al.: Reduced serum selenoprotein P concentrations in German prostate cancer patients. Cancer Epidemiol Biomarkers Prev 18 (9): 2386-90, 2009.  [PUBMED Abstract]

  29. Penney KL, Li H, Mucci LA, et al.: Selenoprotein P genetic variants and mrna expression, circulating selenium, and prostate cancer risk and survival. Prostate 73 (7): 700-5, 2013.  [PUBMED Abstract]

  30. Zhang W, Joseph E, Hitchcock C, et al.: Selenium glycinate supplementation increases blood glutathione peroxidase activities and decreases prostate-specific antigen readings in middle-aged US men. Nutr Res 31 (2): 165-8, 2011.  [PUBMED Abstract]

  31. Hurst R, Hooper L, Norat T, et al.: Selenium and prostate cancer: systematic review and meta-analysis. Am J Clin Nutr 96 (1): 111-22, 2012.  [PUBMED Abstract]

  32. Vidlar A, Vostalova J, Ulrichova J, et al.: The safety and efficacy of a silymarin and selenium combination in men after radical prostatectomy - a six month placebo-controlled double-blind clinical trial. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 154 (3): 239-44, 2010.  [PUBMED Abstract]

  33. Stratton MS, Algotar AM, Ranger-Moore J, et al.: Oral selenium supplementation has no effect on prostate-specific antigen velocity in men undergoing active surveillance for localized prostate cancer. Cancer Prev Res (Phila) 3 (8): 1035-43, 2010.  [PUBMED Abstract]

  34. Algotar AM, Stratton MS, Ahmann FR, et al.: Phase 3 clinical trial investigating the effect of selenium supplementation in men at high-risk for prostate cancer. Prostate 73 (3): 328-35, 2013.  [PUBMED Abstract]

  35. Marshall JR, Tangen CM, Sakr WA, et al.: Phase III trial of selenium to prevent prostate cancer in men with high-grade prostatic intraepithelial neoplasia: SWOG S9917. Cancer Prev Res (Phila) 4 (11): 1761-9, 2011.  [PUBMED Abstract]

  36. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994.  [PUBMED Abstract]

  37. Klein EA: Selenium and vitamin E cancer prevention trial. Ann N Y Acad Sci 1031: 234-41, 2004.  [PUBMED Abstract]

  38. Lippman SM, Klein EA, Goodman PJ, et al.: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301 (1): 39-51, 2009.  [PUBMED Abstract]

  39. Klein EA, Thompson IM Jr, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011.  [PUBMED Abstract]

  40. Lippman SM, Goodman PJ, Klein EA, et al.: Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). J Natl Cancer Inst 97 (2): 94-102, 2005.  [PUBMED Abstract]

  41. Ledesma MC, Jung-Hynes B, Schmit TL, et al.: Selenium and vitamin E for prostate cancer: post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) status. Mol Med 17 (1-2): 134-43, 2011 Jan-Feb.  [PUBMED Abstract]

  42. Hatfield DL, Gladyshev VN: The Outcome of Selenium and Vitamin E Cancer Prevention Trial (SELECT) reveals the need for better understanding of selenium biology. Mol Interv 9 (1): 18-21, 2009.  [PUBMED Abstract]

  43. Ohta Y, Kobayashi Y, Konishi S, et al.: Speciation analysis of selenium metabolites in urine and breath by HPLC- and GC-inductively coupled plasma-MS after administration of selenomethionine and methylselenocysteine to rats. Chem Res Toxicol 22 (11): 1795-801, 2009.  [PUBMED Abstract]

  44. Kristal AR, Darke AK, Morris JS, et al.: Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J Natl Cancer Inst 106 (3): djt456, 2014.  [PUBMED Abstract]

Soy



Overview

This section contains the following key information:

  • Soy foods (e.g., soy milk, miso, tofu, and soy flour) contain phytochemicals that may have health benefits and, among these, soy isoflavones have been the focus of most of the research.

  • Soy isoflavones are phytoestrogens. The major isoflavones in soybeans are genistein (the most abundant), daidzein, and glycitein.

  • Genistein affects components of multiple growth and proliferation -related pathways in prostate cancer cells, including the COX-2 /prostaglandin, epidermal growth factor (EGF), and insulin-like growth factor (IGF) pathways.

  • Some preclinical studies have indicated that the combined effect of multiple isoflavones may be greater than that of a single isoflavone.

  • Some animal studies have demonstrated prostate cancer prevention effects with soy and genistein; however, other animal studies have yielded conflicting results regarding beneficial effects of genistein on prostate cancer metastasis.

  • Epidemiologic studies have generally found high consumption of nonfermented soy foods to be associated with a decreased risk of prostate cancer.

  • Limited human prevention studies have been conducted, and, so far, they have not yielded consistent or definitive findings.

  • Treatment trials of various doses and preparations of soy isoflavones in men with prostate cancer have yielded varying results but have generally failed to demonstrate significant effects on prostate-specific antigen (PSA) levels.

  • A few clinical trials of soy protein or whole soy products have provided preliminary evidence of the ability of these products to lower PSA levels in men with prostate cancer.

  • Soy products are generally well tolerated in patients with prostate cancer. In clinical trials, the most commonly reported side effects were mild gastrointestinal symptoms.

General Information & History

Although records of soy use in China date back to the eleventh century BC, it was not until the 18th century that the plant reached Europe and the United States. The soybean is an incredibly versatile plant: it can be processed into a variety of products including soy milk, miso, tofu, soy flour, and soy oil.[1]

Soy foods contain a number of phytochemicals that may have health benefits but isoflavones have garnered the most attention. Among the isoflavones found in soybeans, genistein is the most abundant and may have the most biological activity.[2] Other isoflavones found in soy include daidzein and glycitein.[3] Isoflavones help soybeans survive in times of stress and have antioxidant, antimicrobial, and antifungal properties.[4]

Isoflavones are quickly taken up by the gut and can be detected in plasma as soon as 30 minutes after the consumption of soy products. Studies suggest that maximum levels of isoflavone plasma concentration may be achieved by 6 hours following soy product consumption.[5] Isoflavones are phytoestrogens (they bind to estrogen receptors) with a greater binding affinity for estrogen receptor beta than for estrogen receptor alpha.[6]

Some studies suggest that soy may have health benefits, including decreasing risk of cardiovascular disease and cancer. A link between isoflavones and cancer was discovered in 1987 when it was shown that genistein inhibited a protein tyrosine kinase that is often overexpressed in cancer cells.[7] Subsequently, genistein was found to inhibit multiple protein tyrosine kinases relevant to cancer cell proliferation.[8] In addition, numerous studies have shown that prostate cancer incidence is very low in Asian countries, where diets tend to be high in soy.[9]

Preclinical/Animal Studies

In vitro studies

Individual isoflavones

A number of laboratory studies have examined ways in which soy components affect prostate cancer cells. In one study, human prostate cancer cells and normal prostate epithelial cells were treated with either an ethanol vehicle (carrier) or isoflavones. Treatment with genistein decreased COX-2 mRNA and protein levels in cancer cells and normal epithelial cells more than did treatment with the vehicle. In addition, cells treated with genistein exhibited reduced secretion of prostaglandin E2 (PGE2) and reduced mRNA levels of the prostaglandin receptors EP4 and FP, suggesting that genistein may exert chemopreventive effects by inhibiting the synthesis of prostaglandins, which promote inflammation.[10] In another study, human prostate cancer cells were treated with genistein or daidzein. The isoflavones were shown to down regulate growth factors involved in angiogenesis (e.g., EGF and IGF-1) and the interleukin -8 gene, which is associated with cancer progression. These findings suggest that genistein and daidzein may have chemopreventive properties.[11] Both genistein and daidzein have been shown to reduce the proliferation of LNCaP and PC-3 prostate cancer cells in vitro . However, during the 72 hours of incubation, only genistein provoked effects on the dynamic phenotype and decreased invasiveness in PC-3 cells. These results imply that invasive activity is at least partially dependent on membrane fluidity and that genistein may exert its antimetastatic effects by changing the mechanical properties of prostate cancer cells. No such effects were observed for daidzein at the same dose.[12]

Combinations of isoflavones

Some experiments have been conducted comparing effects of individual isoflavones with isoflavone combinations on prostate cancer cells. In one such study, human prostate cancer cells were treated with a soy extract (containing genistin, daidzin, and glycitin), genistein, or daidzein. The soy extract induced cell cycle arrest and apoptosis in prostate cancer cells to a greater degree than did treatment with the individual isoflavones. Genistein and daidzein activated apoptosis in noncancerous benign prostatic hyperplasia (BPH) cells, but the soy extract had no effect on those cells. These findings suggest that products containing a combination of active compounds (e.g., "whole foods") may be more effective in preventing cancer than individual compounds.[13] Similarly, in another study, prostate cancer cells were treated with genistein, biochanin A, quercetin, doublets of those compounds (e.g., genistein + quercetin), or with all three compounds. All of the treatments resulted in decreased cell proliferation, but the greatest reductions occurred using the combination of genistein, biochanin A, and quercetin. The triple combination treatment induced more apoptosis in prostate cancer cells than did individual or doublet compound treatments. These results indicate that combining phytoestrogens may increase the effectiveness of the individual compounds.[14]

At least one study has examined the combined effect of soy isoflavones and curcumin. Human prostate cancer cells were treated with isoflavones, curcumin, or a combination of the two. Curcumin and isoflavones in combination were more effective in lowering PSA levels and expression of the androgen receptor than were curcumin or the isoflavones individually.[15]

Animal studies

Animal models of prostate cancer have been used in studies investigating the effects of soy and isoflavones on the disease. Wild-type and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control diets or diets containing genistein (250 mg genistein/kg chow). The TRAMP mice fed with genistein exhibited reduced cell proliferation in the prostate compared with TRAMP mice fed a control diet. The genistein-supplemented diet also reduced levels of ERK-1 and ERK-2 (proteins important in stimulating cell proliferation) as well as the growth factor receptors EGFR and IGF-1R in TRAMP mice, suggesting that down regulation of these proteins may be one mechanism by which genistein exerts chemopreventive effects.[16] In another study, following the appearance of spontaneous prostatic intraepithelial neoplasia lesions, TRAMP mice were fed control diets or diets supplemented with genistein (250 or 1,000 mg genistein/kg chow). Mice fed low-dose genistein exhibited more cancer cell metastasis and greater osteopontin expression than mice fed the control or the high-dose genistein diet. These results indicate that timing and dose of genistein treatment may affect prostate cancer outcomes and that genistein may exert biphasic control over prostate cancer.[17] In a study reported in 2008, athymic mice were implanted with human prostate cancer cells and fed a control or genistein-supplemented diet (100 or 250 mg genistein/kg chow). Mice that were fed genistein exhibited less cancer cell metastasis, but no change in primary tumor volume, than did mice fed a control diet. Furthermore, other data suggested that genistein inhibits metastasis by impairing cancer cell detachment.[18] In contrast, in a study reported in 2011, there were more metastases in secondary organs in genistein-treated mice than in vehicle-treated mice. In this latter study, mice were implanted with human prostate cancer xenografts and treated daily with genistein dissolved in peanut oil (80 mg genistein/kg body weight/day or 400 mg genistein/kg body weight/day) or peanut oil vehicle by gavage. In addition, there was a reduction in tumor cell apoptosis in the genistein-treated mice compared with the vehicle-treated mice. These findings suggest that genistein may stimulate metastasis in an animal model of advanced prostate cancer.[19]

Radiation therapy is commonly used in prostate cancer, but, despite this treatment, disease recurrence is common. Therefore, combining radiation with additional therapies may provide longer-lasting results. In one study, human prostate cancer cells were treated with soy isoflavones and/or radiation. Cells that were treated with both isoflavones and radiation exhibited greater decreases in cell survival and greater expression of proapoptotic molecules than cells treated with isoflavones or radiation only. Nude mice were implanted with prostate cancer cells and treated by gavage with genistein (21.5 mg/kg body weight/day), mixed isoflavones (50 mg/kg body weight/day; contained 43% genistein, 21% daidzein, and 2% glycitein) and/or radiation. Mixed isoflavones were more effective than genistein in inhibiting prostate tumor growth, and combining isoflavones with radiation resulted in the largest inhibition of tumor growth. In addition, mice given soy isoflavones in combination with radiation did not exhibit lymph node metastasis, which was seen previously in other experiments combining genistein with radiation. These preclinical findings suggest that mixed isoflavones may increase the efficacy of radiation therapy for prostate cancer.[20]

Human Studies

Numerous clinical studies have been conducted examining the impact of soy use on indicators of the effectiveness of prostate cancer prevention or treatment approaches. These studies have included a wide range of participants (from healthy control subjects to prostate cancer patients at various stages of the disease) and have used a number of different interventions such as soy supplements, beverages, and breads.

Epidemiologic studies

In 2009, a meta-analysis of studies that investigated soy food consumption and risk of prostate cancer was reported. The results of this meta-analysis suggested that high consumption of nonfermented soy foods (e.g., tofu and soybean milk) may significantly decrease the risk of prostate cancer. No association was found between high consumption of fermented soy foods (e.g., miso) and prostate cancer risk.[21] An updated 2013 meta-analysis confirmed the good safety profile of isoflavones but indicated no significant differences between treated and control groups for PSA levels or sex steroid endpoints (sex hormone-binding globulin, testosterone, free testosterone, estradiol and dihydrotestosterone).[22] In another study, urinary concentrations of phytoestrogens were assessed in healthy Jamaican men and men newly diagnosed with prostate cancer. There were no differences in urinary concentrations of the isoflavones genistein and daidzein between healthy men and prostate cancer patients. Men who produced equol (a metabolite of daidzein) were at a lower risk of prostate cancer than men who were nonproducers.[23]

Prevention studies

In one study, Japanese men who had undergone prostate biopsy, but who did not have cancer, were randomly assigned to receive a supplement containing soy isoflavones (40 mg; comprised of 66% daidzein, 24% glycitin, and 10% genistin) and curcumin (100 mg) or a placebo for 6 months. Overall, there were no differences in PSA levels between the placebo and the treatment groups. However, when subjects were subdivided according to baseline PSA level, patients with a higher baseline PSA level (PSA ≥10 ng/mL) who received supplements exhibited statistically significantly larger decreases in PSA than did patients in the placebo group (P = .02).[15]

Although soy is a standard part of many Asian diets, it is less common in Western diets. Therefore, feasibility studies were undertaken to investigate whether Western participants would adhere to soy-supplementation interventions. In one study, healthy men were randomly assigned to consume a low soy (usual diet) or high-soy (two daily soy servings) diet for 3 months. Following a 1-month washout period, the men crossed over to the other treatment. Reductions approaching statistical significance were seen in PSA levels following the high-soy diet. These findings suggest that this type of soy intervention study is feasible (i.e., the participants complied with dietary instructions) and that soy may be a potential chemopreventive agent.[24]

In another study, men at risk of prostate cancer or with low-grade prostate cancer received one of three types of protein isolate (soy protein, alcohol-washed soy protein [a common method of producing soy protein concentrate that results in some loss of isoflavones], or milk protein) for 6 months. The isoflavone content of the interventions was 107±5.0 mg/day for soy protein isolate (containing 53% genistein, 35% daidzein, and 11% glycitein), <6±0.7 mg/day for alcohol-washed soy protein (containing 57% genistein, 20% daidzein, and 23% glycitein), and 0 mg/day for milk protein. Soy protein consumption did not alter prostate tissue biomarkers, alcohol-washed soy protein exerted mixed effects, and less prostate cancer was detected after 6 months in men who had consumed soy proteins compared with men who consumed milk protein.[25]

Other plants also contain some of the same isoflavones found in soy. In one study, patients with elevated PSA levels but negative prostate biopsy specimens received a daily isoflavone preparation extracted from red clover (60 mg/day; which contained the isoflavones genistein, daidzein, formononetin, and biochanin A) and were followed up for 1 year. Following 12 months of treatment, there was a significant reduction in PSA levels (P = .019) and a nonsignificant decrease in prostate volume (P = .097). In addition, the isoflavone intervention was well tolerated by the patients and did not cause side effects.[26]

Treatment of prostate cancer

Isoflavones

In a study reported in 2010, patients with rising PSA levels who had been treated with radiation as the primary treatment for prostate cancer drank a soy beverage daily (providing approximately 65-90 mg isoflavones) for 6 months. The results showed that the soy beverage was well-tolerated and was associated with an increase in PSA doubling time. These findings suggested that drinking the soy beverage may have helped to slow the progression of prostate cancer.[27]

In one small (n = 20), open-label study, patients with rising PSA levels following previous therapy consumed soy milk three times a day (141 mg isoflavonoid/day) for 12 months. The results showed that drinking soy milk was associated with a greater than 50% decline in PSA level in one patient and decreases in the rate of rise in serum PSA in 14 patients.[28]

In another study, prostate cancer patients received genistein-rich supplements (450 mg genistein/day, plus 450 mg other aglycone isoflavones/day) for 6 months. The majority of patients who were undergoing active surveillance exhibited either no rise in PSA level or a decline of less than 50%.[29] In a similar study, prostate cancer patients undergoing active surveillance were randomly assigned to receive a placebo or an isoflavone supplement containing high doses of genistein and daidzein (450 mg genistein, 300 mg daidzein, and other isoflavones) for 6 months. Then, for an additional 6 months, all participants received the isoflavone supplement. Although treatment with the supplements raised serum concentration levels of genistein and daidzein, there was no effect on PSA levels.[30]

In a study reported in 2011, prostate cancer patients scheduled for radical prostatectomy were randomly assigned to receive a placebo or 30 mg genistein daily for 3 to 6 weeks before surgery. Among the patients who received genistein, serum PSA levels decreased by 7.8%, whereas serum PSA levels increased by 4.4% in patients who received the placebo; this difference approached statistical significance (P = .051). In addition, the genistein intervention resulted in significantly lower levels of total cholesterol compared with placebo treatment (P = .013).[31] Another group, however, conducted a randomized placebo-controlled trial to examine the effect of soy isoflavone capsules (80 mg/day of total isoflavones) on localized prostate cancer in 86 men who took the capsules for up to 6 weeks before prostatectomy.[32] Changes in serum-free and total testosterone, PSA, and total cholesterol were not different between the two groups. The investigators noted that the 12 genes involved in cell cycle control and the 9 genes involved in apoptosis were down regulated in the tumor tissues of the isoflavone-treated men, compared with the controls.

In a phase II, randomized, double-blind, placebo-controlled trial [33,34] of men with localized prostate cancer (Gleason score 2–6) who were administered isoflavones (80 mg/day) or a placebo, significant increases in plasma isoflavones (P ≤ .001) were observed from baseline to 4 and 12 weeks in the isoflavone-treated group compared with placebo. Although greater mean reduction of serum-free testosterone was observed in men in the isoflavone-treated group than in men in the placebo group, these changes were not statistically significant for this duration of intervention (P = 0.3). Increasing concentrations of plasma isoflavones daidzein (P = .02) and genistein (P = .01) in the isoflavone-treated group was inversely correlated with changes in serum PSA, compared with the placebo arm.

In another phase II, multidose, randomized placebo-controlled trial,[33] 45 men with localized prostate cancer received supplements with either 40, 60, or 80 mg of purified isoflavones or no supplement from the time of biopsy to prostatectomy. Significant increases in plasma isoflavones were observed with all isoflavone doses, compared with placebo, and significant increases in serum total estradiol were observed in the 40 mg and 60 mg isoflavone-treated arms. However, significant increases in serum-free testosterone were observed in the 60 mg isoflavone-treated arm. Compared with the control group and other treatment arms, the 40 mg isoflavone-treated arm had the lowest percentage of cells expressing Ki-67, although this was not statistically significant for this sample size and duration of intervention. This study concluded that 40 mg of isoflavones may be the best dose to use in a future definitive, larger phase II clinical trial to evaluate purified isoflavones in prostate carcinogenesis.

Soy protein

In one study, early-stage prostate cancer patients were randomly assigned to receive a soy protein supplement (60 mg/day isoflavones) or a placebo daily for 12 weeks. Patients who received the soy protein supplement exhibited larger decreases in total serum PSA and free testosterone than did patients who received the placebo, but these differences were not statistically significant.[35]

Whole soy products

Clinical studies have been conducted in prostate cancer patients to test soy as a possible treatment for prostate cancer. In one study, prostate cancer patients scheduled to undergo radical prostatectomy were randomly assigned to receive soy supplements (three 27.2 mg tablets/day; each tablet contained 10.6 mg genistein, 13.3 mg daidzein, and 3.2 mg glycitein) or a placebo for 2 weeks before surgery. The isoflavone concentration in prostatic tissue was sixfold higher than in serum following treatment with the soy supplements, suggesting that the prostate may accumulate potentially anticarcinogenic levels of isoflavones.[36] In another study, prostate cancer patients scheduled for radical prostatectomy were instructed to eat bread containing high levels of phytoestrogens (soy or soy + linseed; 117 mg/day isoflavones) or low levels of phytoestrogens (wheat bread) until surgery. Patients who ate the high-phytoestrogen bread saw more favorable changes in PSA levels than did patients who ate the wheat bread, indicating that diets rich in phytoestrogens may help to reduce risk of prostate cancer development and progression.[37]

In another small study, ten men with prostate cancer recurrence were advised to consume three 8-ounce glasses of soy milk every day for 2 years. Clinical benefits (i.e., decreased, attenuated, or stabilized PSA) were observed in five of the ten participants, suggesting that soy products may have positive effects in some prostate cancer patients.[38]

Management of hormone therapy side-effects

Androgen deprivation therapy is commonly used for locally advanced and metastatic prostate cancer. However, this treatment is associated with a number of adverse side effects including sexual dysfunction, decreased quality of life, and changes in cognition. In one study, men undergoing androgen deprivation therapy were randomly assigned to receive a placebo or an isoflavone supplement (soy protein powder mixed with beverages; 160 mg/day isoflavones) for 12 weeks. The study results showed no improvement in side effects following isoflavone treatment compared with placebo treatment.[39] In a 2 X 2 factorial design study that investigated soy protein powder and venlafaxine in 120 androgen-deprived men, neither proved effective alone or in combination in decreasing hot flashes, although the number of vasomotor symptoms decreased significantly in all four arms over the 12-week trial.[40] Soy protein, but not venlafaxine, produced statistically significant improvements in emotional and functional subscales on quality-of-life instruments.

Effects on inflammatory parameters

In another study of men undergoing androgen deprivation therapy, participants were randomly assigned to receive high-dose isoflavone supplements (providing 160 mg/day total isoflavones and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein) or a placebo for 12 weeks. The results showed no difference between the two groups in PSA levels or in levels of metabolic and inflammatory parameters (e.g., glucose, interleukin-6).[41]

Prostaglandins promote inflammation and may contribute to cancer by increasing cell proliferation and inhibiting apoptosis. The findings of a study reported in 2009 suggest that soy isoflavones may have chemopreventive effects via inhibition of the prostaglandin pathway. In the study, prostate cancer patients scheduled to undergo prostatectomy were randomly assigned to receive a placebo or a soy isoflavone supplement (providing 81.6 mg/day isoflavones) for at least 2 weeks before surgery. The results showed a significant decrease in COX-2 mRNA levels (P < .01) and significant increases in p21 mRNA levels (P < .01) in prostatectomy specimens obtained from the soy-supplemented group compared with specimens from the placebo group.[10]

Current Clinical Trials

Check NCI’s list of cancer clinical trials for CAM clinical trials on soy isoflavones for prostate cancer and soy protein isolate for prostate cancer that are actively enrolling patients.

General information about clinical trials is also available from the NCI Web site.

Adverse Effects

Overall, soy was well tolerated in clinical studies of prostate cancer patients.[24,26,28,30,36,39] The most commonly reported side effects were gastrointestinal symptoms.[27,29,30] In addition, one study reported that a participant withdrew due to insomnia.[27]

References
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  14. Kumar R, Verma V, Jain A, et al.: Synergistic chemoprotective mechanisms of dietary phytoestrogens in a select combination against prostate cancer. J Nutr Biochem 22 (8): 723-31, 2011.  [PUBMED Abstract]

  15. Ide H, Tokiwa S, Sakamaki K, et al.: Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate 70 (10): 1127-33, 2010.  [PUBMED Abstract]

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  18. Lakshman M, Xu L, Ananthanarayanan V, et al.: Dietary genistein inhibits metastasis of human prostate cancer in mice. Cancer Res 68 (6): 2024-32, 2008.  [PUBMED Abstract]

  19. Nakamura H, Wang Y, Kurita T, et al.: Genistein increases epidermal growth factor receptor signaling and promotes tumor progression in advanced human prostate cancer. PLoS One 6 (5): e20034, 2011.  [PUBMED Abstract]

  20. Raffoul JJ, Banerjee S, Che M, et al.: Soy isoflavones enhance radiotherapy in a metastatic prostate cancer model. Int J Cancer 120 (11): 2491-8, 2007.  [PUBMED Abstract]

  21. Hwang YW, Kim SY, Jee SH, et al.: Soy food consumption and risk of prostate cancer: a meta-analysis of observational studies. Nutr Cancer 61 (5): 598-606, 2009.  [PUBMED Abstract]

  22. van Die MD, Bone KM, Williams SG, et al.: Soy and soy isoflavones in prostate cancer: a systematic review and meta-analysis of randomized controlled trials. BJU Int 113 (5b): E119-30, 2014.  [PUBMED Abstract]

  23. Jackson MD, McFarlane-Anderson ND, Simon GA, et al.: Urinary phytoestrogens and risk of prostate cancer in Jamaican men. Cancer Causes Control 21 (12): 2249-57, 2010.  [PUBMED Abstract]

  24. Maskarinec G, Morimoto Y, Hebshi S, et al.: Serum prostate-specific antigen but not testosterone levels decrease in a randomized soy intervention among men. Eur J Clin Nutr 60 (12): 1423-9, 2006.  [PUBMED Abstract]

  25. Hamilton-Reeves JM, Rebello SA, Thomas W, et al.: Effects of soy protein isolate consumption on prostate cancer biomarkers in men with HGPIN, ASAP, and low-grade prostate cancer. Nutr Cancer 60 (1): 7-13, 2008.  [PUBMED Abstract]

  26. Engelhardt PF, Riedl CR: Effects of one-year treatment with isoflavone extract from red clover on prostate, liver function, sexual function, and quality of life in men with elevated PSA levels and negative prostate biopsy findings. Urology 71 (2): 185-90; discussion 190, 2008.  [PUBMED Abstract]

  27. Kwan W, Duncan G, Van Patten C, et al.: A phase II trial of a soy beverage for subjects without clinical disease with rising prostate-specific antigen after radical radiation for prostate cancer. Nutr Cancer 62 (2): 198-207, 2010.  [PUBMED Abstract]

  28. Pendleton JM, Tan WW, Anai S, et al.: Phase II trial of isoflavone in prostate-specific antigen recurrent prostate cancer after previous local therapy. BMC Cancer 8: 132, 2008.  [PUBMED Abstract]

  29. deVere White RW, Hackman RM, Soares SE, et al.: Effects of a genistein-rich extract on PSA levels in men with a history of prostate cancer. Urology 63 (2): 259-63, 2004.  [PUBMED Abstract]

  30. deVere White RW, Tsodikov A, Stapp EC, et al.: Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone concentrations in men with localized prostate cancer. Nutr Cancer 62 (8): 1036-43, 2010.  [PUBMED Abstract]

  31. Lazarevic B, Boezelijn G, Diep LM, et al.: Efficacy and safety of short-term genistein intervention in patients with localized prostate cancer prior to radical prostatectomy: a randomized, placebo-controlled, double-blind Phase 2 clinical trial. Nutr Cancer 63 (6): 889-98, 2011.  [PUBMED Abstract]

  32. Hamilton-Reeves JM, Banerjee S, Banerjee SK, et al.: Short-term soy isoflavone intervention in patients with localized prostate cancer: a randomized, double-blind, placebo-controlled trial. PLoS One 8 (7): e68331, 2013.  [PUBMED Abstract]

  33. Kumar NB, Krischer JP, Allen K, et al.: A Phase II randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer. Nutr Cancer 59 (2): 163-8, 2007.  [PUBMED Abstract]

  34. Kumar NB, Krischer JP, Allen K, et al.: Safety of purified isoflavones in men with clinically localized prostate cancer. Nutr Cancer 59 (2): 169-75, 2007.  [PUBMED Abstract]

  35. Kumar NB, Cantor A, Allen K, et al.: The specific role of isoflavones in reducing prostate cancer risk. Prostate 59 (2): 141-7, 2004.  [PUBMED Abstract]

  36. Gardner CD, Oelrich B, Liu JP, et al.: Prostatic soy isoflavone concentrations exceed serum levels after dietary supplementation. Prostate 69 (7): 719-26, 2009.  [PUBMED Abstract]

  37. Dalais FS, Meliala A, Wattanapenpaiboon N, et al.: Effects of a diet rich in phytoestrogens on prostate-specific antigen and sex hormones in men diagnosed with prostate cancer. Urology 64 (3): 510-5, 2004.  [PUBMED Abstract]

  38. Joshi M, Agostino NM, Gingrich R, et al.: Effects of commercially available soy products on PSA in androgen-deprivation-naïve and castration-resistant prostate cancer. South Med J 104 (11): 736-40, 2011.  [PUBMED Abstract]

  39. Sharma P, Wisniewski A, Braga-Basaria M, et al.: Lack of an effect of high dose isoflavones in men with prostate cancer undergoing androgen deprivation therapy. J Urol 182 (5): 2265-72, 2009.  [PUBMED Abstract]

  40. Vitolins MZ, Griffin L, Tomlinson WV, et al.: Randomized trial to assess the impact of venlafaxine and soy protein on hot flashes and quality of life in men with prostate cancer. J Clin Oncol 31 (32): 4092-8, 2013.  [PUBMED Abstract]

  41. Napora JK, Short RG, Muller DC, et al.: High-dose isoflavones do not improve metabolic and inflammatory parameters in androgen-deprived men with prostate cancer. J Androl 32 (1): 40-8, 2011 Jan-Feb.  [PUBMED Abstract]

Vitamin D



Overview
General Information and History

Vitamin D, also called calciferol, cholecalciferol (D3), or ergocalciferol (D2), is a fat-soluble vitamin found in fortified dairy products, fatty fish, fish liver oil, and eggs. Vitamin D is made naturally by the body when exposed to sunlight.

In 1922, researchers discovered that heated, oxidized cod-liver oil, called "fat-soluble factor A" and later known as vitamin D, played an important role in curing rickets in rats.[1]

Vitamin D performs many roles in the body, including the following:

Vitamin D is needed for bone growth and protects against osteoporosis in adults.[2] Vitamin D status is usually checked by measuring the level of 25-hydroxyvitamin D in the blood.

Preclinical/Animal Studies

In vitro studies

To study the role of vitamin D in cancer cell adhesion to endothelium, one study developed a microtube system that simulates the microvasculature of bone marrow. The study reported that 1,25-alpha-dihydroxyvitamin D3 (1,25-D3) suppressed adhesion of prostate cancer cells in the microtube system. In addition, it was shown that 1,25-D3 increased E-cadherin expression, which may prevent prostate cancer cell adhesion to endothelium by promoting cancer cell aggregation.[3]

Vitamin D–binding protein (DBP) transports vitamin D in the bloodstream. Studies have shown that one of its products, DBP-macrophage activating factor (DBP-maf), may have antiangiogenic and antitumor activities. One study examined the effects of DBP-maf on prostate cancer cells. Treating prostate cancer cells with DBP-maf resulted in inhibited cellular migration, proliferation, and reduced levels of urokinase plasminogen activator receptor (uPAR; activity of this receptor correlates with tumor metastasis). These findings suggest that DBP-maf has a direct effect on prostate cancer cells.[4]

Studies have reported that 1,25-D3 may play an important role in prostate cancer biology. Studies have suggested that a newly discovered protein, protein disulfide isomerase family A, member 3 (PDIA3), may function as a membrane receptor binding to 1,25-D3. According to one study, PDIA3 is expressed in normal prostate cells as well as in LNCaP and PC-3 prostate cancer cell lines. In addition, their findings suggest that 1,25-D3 may act on prostate cancer cells via multiple signaling pathways, indicating there may be a number of potential therapeutic targets.[5]

In vivo studies

Tumor progression was compared in two murine models of prostate cancer. In vitamin D receptor- knockout animals, rate of tumor progression and cellular proliferation were greater than in wild type animals. However, in mice that were supplemented with testosterone, these differences did not occur, suggesting that there may be significant interaction between androgen signaling and vitamin D signaling.[6]

In a 2011 study, nude mice were fed a control diet or a diet deficient in vitamin D and were then injected with prostate cancer cells into bone marrow or into soft tissues. Osteolytic lesions were larger and progressed at a faster rate in vitamin D–deficient mice that had bone marrow injected with cancer cells than in mice that had adequate levels of vitamin D. However, there was no difference in soft tissue tumors among mice with different vitamin D levels. Results of this study show that vitamin D deficiency is associated with growth of prostate cancer cells in bone but not in soft tissue.[7]

A 2014 study evaluated calcitriol and a less-calcemic vitamin D analog in an aggressive transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Neither vitamin D analog impacted the rate of development of castration -resistant prostate cancer in mice, whether they were treated before or after castration. However, both vitamin D analogs slowed progression of primary tumors in hormone-intact mice but enhanced distant organ metastases after prolonged treatment. In sum, intervention with potent vitamin D compounds in TRAMP mice slowed androgen-stimulated tumor progression but, over time, may have led to more aggressive disease as indicated by increased distant metastases (P = .0823).[8] This preclinical data supports findings of the 2008 retrospective study [9] of an association between serum vitamin D levels and aggressive prostate cancer (refer to the Human Studies section in the Vitamin D section of this summary for more information about this study).

Vitamin D as adjuvant therapy

Cryotherapy may be used for treating prostate cancer. Studies have been conducted to identify potential agents that may help improve efficacy of the freezing procedure. In a 2010 study, mice were injected with prostate cancer cells and treated with calcitriol, cryoablation, or both. The combination treatment group experienced larger necrotic areas, more apoptosis, and less cell proliferation than did the other experimental groups.[10] A subsequent study corroborated these findings, showing that combining calcitriol and cryoablation resulted in more cell death than cryotherapy alone.[11]

Vitamin D may help enhance other types of cancer treatments, such as radiation. In another study, prostate cancer cells were treated with valproic acid (VPA) and/or 1,25-D3, followed by radiation. Cells that were treated with VPA and/or 1,25-D3 and radiation had greater decreases in cell proliferation than did cells treated solely with radiation. The greatest reduction in cell proliferation occurred in cells treated with VPA, 1,25-D3, and radiation.[12]

Human Studies

Epidemiological studies

The relationship between vitamin D and prostate cancer has been examined in numerous epidemiological studies. Vitamin D levels were analyzed annually for 5 years in patients with nonmetastatic prostate cancer. Results showed that throughout the course of the study, vitamin D insufficiency was prevalent among these cancer patients.[13] Levels of vitamin D metabolites in prostate cancer patients were examined in a 2011 study. Analysis revealed that patients with the lowest concentrations of prediagnostic plasma 25-hydroxy vitamin D [25(OH)D] levels had a higher risk of developing metastatic prostate cancer than did patients with higher levels of 25(OH)D. However, there was no association between metastatic prostate cancer and circulating levels of 1,25(OH)D.[14] In another study, serum levels of 25(OH)D in prostate cancer patients were assessed. Results suggest that medium or high levels of serum 25(OH)D may be associated with better prognoses than lower levels of serum 25(OH)D. These findings indicate that 25(OH)D may play a role in disease progression and may be a marker of prognosis in prostate cancer patients.[15] Participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study who had been diagnosed with prostate cancer and control participants were selected for analysis and monitored for up to 20 years. Results suggested that men with a higher vitamin D status (assessed via serum 25(OH)D concentrations) had a greater risk of developing prostate cancer than did men with lower vitamin D status.[16] A 2008 retrospective study of 749 men with prostate cancer diagnosed 1 to 8 years after blood draw and 781 matched controls found higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease.[9] Both of these studies [9,16] were included in a meta-analysis of 21 studies, involving 11,941 cases and 13,870 controls, that found a 17% elevated risk of prostate cancer in men with higher levels of 25(OH)D.[17] One explanation offered for this finding may be a potential detection bias with men from higher socio-economic groups who have higher vitamin D levels and who are more likely to undergo prostate-specific antigen (PSA) testing, resulting in higher reported incidence rates.

Serum 25(OH)D levels were obtained from 667 men in Chicago undergoing first prostate biopsy for an elevated PSA or an abnormal digital rectal exam.[18] Severe vitamin D deficiency (<12 ng/mL) was associated with increased risk of a prostate cancer diagnosis on biopsy among African American men. Severe deficiency was positively associated with higher Gleason score (≥4+4), higher clinical stage (>cT2b), and overall risk category in both white American and African American men. In contrast, baseline serum 25(OH)D levels obtained in a case (n = 1,731)–cohort (n = 3,203) analysis from the Selenium and Vitamin E Cancer Prevention Trial found significantly reduced risks among men who had moderate concentrations (45–70 nmol/L) compared with men who had lower or higher values.[19] This U-shaped association was most pronounced for cancers with Gleason scores of 7 to 10.

An important means of obtaining vitamin D is via sunlight. Studies have investigated the potential link between sunlight exposure and prostate cancer. According to a 2006 study, PSA levels rise at a slower rate during spring and summer than at other times of the year; this may be related to higher vitamin D levels obtained during those months.[20] Another study found that while men with low levels of sun exposure had increased risk of all prostate cancers, among men with prostate cancer, less sun exposure was associated with lower risk of advanced disease. Results of a meta-analysis, published in the same report, showed that men with low sun exposure had an increased risk of incident and advanced prostate cancer.[21] Analysis of mortality rate data from 1950 to 1994 revealed that the geographic distribution of prostate cancer mortality in the United States is inversely related to UV radiation. In addition, this relationship is more evident in areas north of 40 degrees N latitude.[22] Likewise, a study in France reported that UV radiation may be associated with reductions in cancer risk and mortality.[23]

A number of studies have explored a possible connection between the vitamin D receptor (VDR) and risk of prostate cancer. A 2011 prospective study examined VDR expression in prostate tumors. Patients with high levels of VDR expression had lower PSA at diagnosis, less advanced tumor stage, and reduced risk of lethal prostate cancer compared with patients with lower levels of VDR expression in tumors.[24] In a 2009 study, genetic variants in VDR were analyzed in prostate cancer patients participating in the Prostate Testing for Cancer and Treatment (ProtecT) trial. Five polymorphisms of VDR were identified in the participants. A meta-analysis, published in the same report, revealed no association between specific variants and prostate cancer stage (TNM staging system), but found that three genotypes (BSML, APAL, and TAQL) may be associated with cancer grade (Gleason score), suggesting there may be a link between specific VDR polymorphisms and advanced prostate cancer at diagnosis.[25] Polymorphisms in the VDR receptor, the vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1) were examined in a 2010 study. Variations in the three genes investigated were associated with changes in risk of recurrence and progression of prostate cancer as well as prostate cancer mortality.[26]

A 2008 meta-analysis of 45 observational studies found no association between intake of vitamin D and prostate cancer risk.[27] A meta-analysis published in 2011 reviewed 25 studies examining the link between prostate cancer incidence and indicators of vitamin D. Analysis of those studies found no association between dietary vitamin D or circulating concentrations of vitamin D and risk of prostate cancer.[28]

Intervention studies

Calcitriol, the hormonally active form of vitamin D, has been the focus of some studies in prostate cancer patients. In an open-label, phase II study, patients with recurrent prostate cancer were treated with calcitriol and naproxen for 1 year. The combination of calcitriol and naproxen was effective in decreasing the rate of rising PSA levels in study participants, suggesting it may slow disease progression.[29] In a 2010 study, patients with castration-resistant prostate cancer were treated with calcitriol and dexamethasone. The results indicated that while the treatments were well tolerated, they did not have an effect on participants' PSA levels.[30]

In a 2009 study, patients with locally advanced or metastatic prostate cancer and asymptomatic progression of their PSA levels were treated with vitamin D2 (ergocalciferol) at either 10 μg or 25 μg daily. The investigators reported that about 20% of these patients had at least a 25% drop in PSA level 3 months after initiating the vitamin D2.[31]

Current Clinical Trials

Check NCI’s list of cancer clinical trials for CAM clinical trials on vitamin D that are actively enrolling patients.

General information about clinical trials is also available from the NCI Web site.

References
  1. Wolf G: The discovery of vitamin D: the contribution of Adolf Windaus. J Nutr 134 (6): 1299-302, 2004.  [PUBMED Abstract]

  2. National Institutes of Health. Office of Dietary Supplements: Dietary Supplement Fact Sheet: Vitamin D. Bethesda, MD: National Institutes of Health, 2011. Available online. Last accessed October 9, 2014. 

  3. Hsu JW, Yasmin-Karim S, King MR, et al.: Suppression of prostate cancer cell rolling and adhesion to endothelium by 1α,25-dihydroxyvitamin D3. Am J Pathol 178 (2): 872-80, 2011.  [PUBMED Abstract]

  4. Gregory KJ, Zhao B, Bielenberg DR, et al.: Vitamin D binding protein-macrophage activating factor directly inhibits proliferation, migration, and uPAR expression of prostate cancer cells. PLoS One 5 (10): e13428, 2010.  [PUBMED Abstract]

  5. Karlsson S, Olausson J, Lundh D, et al.: Vitamin D and prostate cancer: the role of membrane initiated signaling pathways in prostate cancer progression. J Steroid Biochem Mol Biol 121 (1-2): 413-6, 2010.  [PUBMED Abstract]

  6. Mordan-McCombs S, Brown T, Wang WL, et al.: Tumor progression in the LPB-Tag transgenic model of prostate cancer is altered by vitamin D receptor and serum testosterone status. J Steroid Biochem Mol Biol 121 (1-2): 368-71, 2010.  [PUBMED Abstract]

  7. Zheng Y, Zhou H, Ooi LL, et al.: Vitamin D deficiency promotes prostate cancer growth in bone. Prostate 71 (9): 1012-21, 2011.  [PUBMED Abstract]

  8. Ajibade AA, Kirk JS, Karasik E, et al.: Early growth inhibition is followed by increased metastatic disease with vitamin D (calcitriol) treatment in the TRAMP model of prostate cancer. PLoS One 9 (2): e89555, 2014.  [PUBMED Abstract]

  9. Ahn J, Peters U, Albanes D, et al.: Serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst 100 (11): 796-804, 2008.  [PUBMED Abstract]

  10. Kimura M, Rabbani Z, Mouraviev V, et al.: Role of vitamin D(3) as a sensitizer to cryoablation in a murine prostate cancer model: preliminary in vivo study. Urology 76 (3): 764.e14-20, 2010.  [PUBMED Abstract]

  11. Santucci KL, Snyder KK, Baust JM, et al.: Use of 1,25α dihydroxyvitamin D3 as a cryosensitizing agent in a murine prostate cancer model. Prostate Cancer Prostatic Dis 14 (2): 97-104, 2011.  [PUBMED Abstract]

  12. Gavrilov V, Leibovich Y, Ariad S, et al.: A combined pretreatment of 1,25-dihydroxyvitamin D3 and sodium valproate enhances the damaging effect of ionizing radiation on prostate cancer cells. J Steroid Biochem Mol Biol 121 (1-2): 391-4, 2010.  [PUBMED Abstract]

  13. Choo CS, Mamedov A, Chung M, et al.: Vitamin D insufficiency is common in patients with nonmetastatic prostate cancer. Nutr Res 31 (1): 21-6, 2011.  [PUBMED Abstract]

  14. Fang F, Kasperzyk JL, Shui I, et al.: Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer. PLoS One 6 (4): e18625, 2011.  [PUBMED Abstract]

  15. Tretli S, Hernes E, Berg JP, et al.: Association between serum 25(OH)D and death from prostate cancer. Br J Cancer 100 (3): 450-4, 2009.  [PUBMED Abstract]

  16. Albanes D, Mondul AM, Yu K, et al.: Serum 25-hydroxy vitamin D and prostate cancer risk in a large nested case-control study. Cancer Epidemiol Biomarkers Prev 20 (9): 1850-60, 2011.  [PUBMED Abstract]

  17. Xu Y, Shao X, Yao Y, et al.: Positive association between circulating 25-hydroxyvitamin D levels and prostate cancer risk: new findings from an updated meta-analysis. J Cancer Res Clin Oncol 140 (9): 1465-77, 2014.  [PUBMED Abstract]

  18. Murphy AB, Nyame Y, Martin IK, et al.: Vitamin D deficiency predicts prostate biopsy outcomes. Clin Cancer Res 20 (9): 2289-99, 2014.  [PUBMED Abstract]

  19. Kristal AR, Till C, Song X, et al.: Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 23 (8): 1494-504, 2014.  [PUBMED Abstract]

  20. Vieth R, Choo R, Deboer L, et al.: Rise in prostate-specific antigen in men with untreated low-grade prostate cancer is slower during spring-summer. Am J Ther 13 (5): 394-9, 2006 Sep-Oct.  [PUBMED Abstract]

  21. Gilbert R, Metcalfe C, Oliver SE, et al.: Life course sun exposure and risk of prostate cancer: population-based nested case-control study and meta-analysis. Int J Cancer 125 (6): 1414-23, 2009.  [PUBMED Abstract]

  22. Schwartz GG, Hanchette CL: UV, latitude, and spatial trends in prostate cancer mortality: all sunlight is not the same (United States). Cancer Causes Control 17 (8): 1091-101, 2006.  [PUBMED Abstract]

  23. Grant WB: An ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. Dermatoendocrinol 2 (2): 62-7, 2010.  [PUBMED Abstract]

  24. Hendrickson WK, Flavin R, Kasperzyk JL, et al.: Vitamin D receptor protein expression in tumor tissue and prostate cancer progression. J Clin Oncol 29 (17): 2378-85, 2011.  [PUBMED Abstract]

  25. Chen L, Davey Smith G, Evans DM, et al.: Genetic variants in the vitamin d receptor are associated with advanced prostate cancer at diagnosis: findings from the prostate testing for cancer and treatment study and a systematic review. Cancer Epidemiol Biomarkers Prev 18 (11): 2874-81, 2009.  [PUBMED Abstract]

  26. Holt SK, Kwon EM, Koopmeiners JS, et al.: Vitamin D pathway gene variants and prostate cancer prognosis. Prostate 70 (13): 1448-60, 2010.  [PUBMED Abstract]

  27. Huncharek M, Muscat J, Kupelnick B: Dairy products, dietary calcium and vitamin D intake as risk factors for prostate cancer: a meta-analysis of 26,769 cases from 45 observational studies. Nutr Cancer 60 (4): 421-41, 2008.  [PUBMED Abstract]

  28. Gilbert R, Martin RM, Beynon R, et al.: Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose-response meta-analysis. Cancer Causes Control 22 (3): 319-40, 2011.  [PUBMED Abstract]

  29. Srinivas S, Feldman D: A phase II trial of calcitriol and naproxen in recurrent prostate cancer. Anticancer Res 29 (9): 3605-10, 2009.  [PUBMED Abstract]

  30. Chadha MK, Tian L, Mashtare T, et al.: Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (calcitriol) in combination with dexamethasone for castration-resistant prostate cancer. Cancer 116 (9): 2132-9, 2010.  [PUBMED Abstract]

  31. Newsom-Davis TE, Kenny LM, Ngan S, et al.: The promiscuous receptor. BJU Int 104 (9): 1204-7, 2009.  [PUBMED Abstract]

Vitamin E



Overview
  • Most dietary vitamin E comes from gamma-tocopherol. Food sources of vitamin E include vegetable oil, nuts, and egg yolks.

  • Research suggests that vitamin E may protect against a number of chronic diseases, such as cardiovascular disease.

  • Studies suggest that alpha-tocopherol –associated protein (TAP) may have capabilities as a tumor suppressor in prostate cancer.

  • The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large multicenter clinical trial, was initiated by the National Institutes of Health (NIH) in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer.

  • In 2011, updated results from SELECT showed that men who took vitamin E alone had a 17% increase in prostate cancer risk compared with men who took placebo.

  • In 2014, an analysis of SELECT results showed that men who had high selenium status at baseline and who were randomly assigned to receive selenium supplementation had an increased risk of high-grade prostate cancer, but vitamin E supplementation had no effect among men with high selenium status.

General Information and History

Vitamin E was discovered in 1922 as a factor essential for reproduction.[1]

Vitamin E occurs in eight different forms: four tocopherols (alpha-, beta-, gamma-, and sigma-) and four tocotrienols (alpha-, beta-, gamma-, and sigma-).[2] Compared with other tocopherols, alpha-tocopherol (the form of vitamin E commonly found in dietary supplements) is the most abundant in the body and the most biologically active. Most dietary vitamin E comes from gamma-tocopherol. Food sources of vitamin E include vegetable oil, nuts, and egg yolks.[3].

The bioavailability of vitamin E depends on a number of factors, such as the food matrix containing vitamin E (e.g., low- or high-fat food).[4] Vitamin E is delivered to tissues by high- and low-density lipoproteins (HDL and LDL, respectively). Delivery by LDL occurs via an endocytic pathway, while the protein’s ATP -binding cassette, subfamily 1 (ABCA1) and scavenger receptor class B type 1 (SR-BI) are involved in HDL vitamin E transport.[5]

Research suggests that vitamin E may protect against a number of chronic diseases, such as cardiovascular disease.[1] Many of vitamin E’s health benefits have been ascribed to its actions as a powerful antioxidant; as with other antioxidants, vitamin E protects cell membranes by interfering with reactions that would form lipid hydroperoxide products.[5] Vitamin E also has nonantioxidant functions: it has been shown to modulate signaling pathways and gene expression.[3]

Human Studies

Epidemiologic studies

The NIH-AARP Diet and Health Study was initiated to examine whether supplemental vitamin E and dietary tocopherol intakes may prevent prostate cancer. Participants in the study completed food-frequency questionnaires and were monitored for 5 years. No association between vitamin E supplements and prostate cancer risk was found. However, a reduction in the risk of advanced prostate cancer was observed with high intakes of gamma-tocopherol.[6]

In a 2010 study, levels of trace elements and vitamin E were measured in prostate cancer patients. Prostate cancer patients had significantly lower levels of plasma vitamin E than did healthy controls. In addition, there was an inverse association between prostate-specific antigen levels and plasma vitamin E.[7]

Studies suggest that alpha-tocopherol–associated protein (TAP) may have capabilities as a tumor suppressor in prostate cancer. In a 2007 study, prostate cancer specimens, which had been obtained from radical prostatectomy, were examined for TAP expression. Results showed reduced TAP expression in prostate cancer tissue and lower levels of TAP were associated with higher clinical stage and larger tumor size.[8]

A study published in 2011 examined serum alpha-tocopherol and supplemental vitamin E intake with sex steroid hormones in participants in the Third National Health and Nutrition Examination Survey (NHANES III). Results showed an inverse association between serum alpha-tocopherol levels and sex steroid hormones, but only in smokers.[9]

Serum alpha-tocopherol and gamma-tocopherol levels and prostate cancer risk were examined in participants in the Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial. An inverse relationship was observed between alpha-tocopherol levels and prostate cancer, but only in current and recently former smokers.[10] A meta-analysis of nine nested case-control studies, representing approximately 370,000 men from several countries, also found an inverse relationship between blood alpha-tocopherol levels and prostate cancer risk, but in all patients studied rather than limited to a smoking subset.[11] No association was seen with gamma-tocopherol levels in this analysis. The risk of prostate cancer decreased by 21% for every 25 mg/L increase in blood alpha-tocopherol levels.

Intervention Studies

The Physicians’ Health Study II investigated whether vitamin C or vitamin E prevents prostate cancer and other cancers in men. Participants in the study were randomly assigned to receive vitamin E (400 IU synthetic alpha-tocopherol taken every other day) and/or vitamin C (500 mg synthetic ascorbic acid taken daily) supplements and were monitored for an average of 8 years. The overall rates of prostate cancer were very similar in the vitamin E supplement and placebo groups, suggesting that vitamin E may not prevent prostate cancer. Furthermore, vitamin E did not have an effect on total cancer or mortality in these participants.[12]

Although not primarily designed for this purpose, the Alpha-Tocopherol, Beta Carotene Cancer Prevention (ATBC) Study has been a resource for researchers investigating prostate cancer and vitamin E.[13] A long follow-up study of participants in the ATBC Study was conducted. Baseline serum alpha-tocopherol levels and dietary intake of vitamin E had been assessed and participants were monitored for up to 19 years. Findings revealed that while there was no association between dietary vitamin E levels and prostate cancer risk, higher serum alpha-tocopherol levels may be associated with a decreased risk for developing advanced prostate cancer.[14] In a 2009 study, blood samples obtained from participants in the ATBC Study were analyzed and genotyped. Results showed that genetic variations in the TTPA and SEC14L2 genes were associated with serum alpha-tocopherol but did not directly affect prostate cancer risk. However, results suggested that polymorphisms in SEC14L2 may influence the effect of alpha-tocopherol supplementation on prostate cancer risk.[15] One study also focused on the ATBC Study and investigated whether serum alpha-tocopherol levels affected survival time in men diagnosed with prostate cancer. Serum alpha-tocopherol levels were assessed at baseline and 3 years later. Higher serum alpha-tocopherol levels, at both baseline and the 3-year point, were associated with improved prostate cancer survival.[16]

A 2011 study examined links between serum alpha- and gamma-tocopherols and risk of prostate cancer among participants in the Carotene and Retinol Efficacy Trial (CARET). CARET was a randomized, placebo-controlled study that investigated whether daily supplementation of beta-carotene and retinyl palmitate would reduce the risk of lung cancer in heavy smokers and asbestos -exposed workers. Results indicated that among current smokers, higher levels of serum alpha- and gamma-tocopherols were associated with reduced risk of aggressive prostate cancer. In addition, findings suggested there may be an interaction between myeloperoxidase (MGO) G-463A genotype, serum alpha-tocopherol level, and prostate cancer risk. Specific genotypes were associated with increased prostate cancer risk in subjects with low levels of serum alpha-tocopherol, while those same genotypes along with higher levels of alpha-tocopherol were associated with reduced risk of prostate cancer.[17]

The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

On the basis of findings from earlier studies,[13,18] the SELECT, a large multicenter clinical trial, was initiated by the NIH in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer. SELECT was a phase III, randomized, double-blind, placebo-controlled, population-based trial.[19] More than 35,000 men, aged 50 years or older, from more than 400 study sites in the United States, Canada, and Puerto Rico were randomly assigned to receive vitamin E (all-rac-alpha-tocopherol acetate, 400 IU daily) and a placebo, selenium (L-selenomethionine, 200 µg daily) and a placebo, vitamin E and selenium, or two placebos daily for 7 to 12 years. The primary endpoint of the clinical trial was incidence of prostate cancer.[19]

Initial results of SELECT were published in 2009. There were no statistically significant differences in rates of prostate cancer in the four groups. In the vitamin E–alone group, there was a nonsignificant increase in rates of prostate cancer (P = .06); in the selenium–alone group, there was a nonsignificant increase in incidence of diabetes mellitus (P = .16). On the basis of those findings, the data and safety monitoring committee recommended that participants stop taking the study supplements. [20]

Updated results were published in 2011. When compared with placebo, the rate of prostate cancer detection was significantly greater in the vitamin E–alone group (P = .008) and represented a 17% increase in prostate cancer risk. There was also greater incidence of prostate cancer in men who had taken selenium than in men who had taken placebo, but those differences were not statistically significant.[21]

Toenail selenium levels were assayed in a two-case cohort study of a subset of SELECT participants. Vitamin E supplementation (alone) had no effect among men with high selenium status at baseline but increased the risks of total (63%; P = .02), low-grade (46%; P = .09), and high-grade (111%; P = .008) prostate cancer among men with lower baseline selenium status. The authors concluded that men older than 55 years should avoid supplementation with either vitamin E or selenium at doses exceeding dietary recommendations.[22]

The dose and form of vitamin E used in SELECT may have contributed to the results. On the basis of the results of the ATBC Study, all-rac-alpha-tocopheryl acetate was the form of vitamin E used in SELECT. The dose used in SELECT (400 IU) was higher than that in the ATBC Study. SELECT researchers opted for the higher dose because it was found in vitamin supplements, there was evidence for benefits of higher doses (including reductions in Alzheimer’s disease and age-related macular degeneration), and it was thought the higher dose would be more protective against prostate cancer than a lower dose.[23] Following the results of SELECT, it has been posited that high levels of alpha-tocopherol may affect levels of gamma-tocopherol, another form of vitamin E that may have chemopreventive effects.[24] Another important difference between the ATBC Study and SELECT that may explain the findings was the smoking status of study participants. Participants in the ATBC Study were smokers, while 7.5% of SELECT participants used tobacco products.[25]

Current Clinical Trials

Check NCI’s list of cancer clinical trials for CAM clinical trials on vitamin E that are actively enrolling patients.

General information about clinical trials is also available from the NCI Web site.

Adverse Effects

Alpha-tocopherols have been deemed Generally Recognized as Safe by the U.S. Food and Drug Administration.[26]

In the Physicians’ Health Study II, there were no significant effects reported for gastrointestinal tract symptoms, fatigue, drowsiness, skin discoloration or rashes, or migraine. However, participants who took vitamin E (400 IU of alpha-tocopherol every other day) experienced a greater number of hemorrhagic strokes than did participants who took placebo.[12] An increase in hemorrhagic strokes among participants in the vitamin E group (50 mg of alpha-tocopherol daily) also was noted in the ATBC Study.[13]

In the initial report of results from SELECT, there were no significant differences between incidences of less severe adverse effects (e.g., alopecia, dermatitis, and nausea) experienced by the groups that received vitamin E (400 IU of all rac-alpha-tocopheryl acetate per day) and those experienced by the other treatment groups.[20] Follow-up analysis of SELECT participants revealed an increased risk of prostate cancer among men in the vitamin E–alone group.[21]

References
  1. Pekmezci D: Vitamin E and immunity. Vitam Horm 86: 179-215, 2011.  [PUBMED Abstract]

  2. Crispen PL, Uzzo RG, Golovine K, et al.: Vitamin E succinate inhibits NF-kappaB and prevents the development of a metastatic phenotype in prostate cancer cells: implications for chemoprevention. Prostate 67 (6): 582-90, 2007.  [PUBMED Abstract]

  3. Ni J, Yeh S: The roles of alpha-vitamin E and its analogues in prostate cancer. Vitam Horm 76: 493-518, 2007.  [PUBMED Abstract]

  4. Mustacich DJ, Bruno RS, Traber MG: Vitamin E. Vitam Horm 76: 1-21, 2007.  [PUBMED Abstract]

  5. Traber MG: Vitamin E. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 841-50. 

  6. Wright ME, Weinstein SJ, Lawson KA, et al.: Supplemental and dietary vitamin E intakes and risk of prostate cancer in a large prospective study. Cancer Epidemiol Biomarkers Prev 16 (6): 1128-35, 2007.  [PUBMED Abstract]

  7. Adaramoye OA, Akinloye O, Olatunji IK: Trace elements and vitamin E status in Nigerian patients with prostate cancer. Afr Health Sci 10 (1): 2-8, 2010.  [PUBMED Abstract]

  8. Wen XQ, Li XJ, Su ZL, et al.: Reduced expression of alpha-tocopherol-associated protein is associated with tumor cell proliferation and the increased risk of prostate cancer recurrence. Asian J Androl 9 (2): 206-12, 2007.  [PUBMED Abstract]

  9. Mondul AM, Rohrmann S, Menke A, et al.: Association of serum α-tocopherol with sex steroid hormones and interactions with smoking: implications for prostate cancer risk. Cancer Causes Control 22 (6): 827-36, 2011.  [PUBMED Abstract]

  10. Weinstein SJ, Peters U, Ahn J, et al.: Serum α-tocopherol and γ-tocopherol concentrations and prostate cancer risk in the PLCO Screening Trial: a nested case-control study. PLoS One 7 (7): e40204, 2012.  [PUBMED Abstract]

  11. Cui R, Liu ZQ, Xu Q: Blood α-tocopherol, γ-tocopherol levels and risk of prostate cancer: a meta-analysis of prospective studies. PLoS One 9 (3): e93044, 2014.  [PUBMED Abstract]

  12. Gaziano JM, Glynn RJ, Christen WG, et al.: Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. JAMA 301 (1): 52-62, 2009.  [PUBMED Abstract]

  13. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994.  [PUBMED Abstract]

  14. Weinstein SJ, Wright ME, Lawson KA, et al.: Serum and dietary vitamin E in relation to prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16 (6): 1253-9, 2007.  [PUBMED Abstract]

  15. Wright ME, Peters U, Gunter MJ, et al.: Association of variants in two vitamin e transport genes with circulating vitamin e concentrations and prostate cancer risk. Cancer Res 69 (4): 1429-38, 2009.  [PUBMED Abstract]

  16. Watters JL, Gail MH, Weinstein SJ, et al.: Associations between alpha-tocopherol, beta-carotene, and retinol and prostate cancer survival. Cancer Res 69 (9): 3833-41, 2009.  [PUBMED Abstract]

  17. Cheng TY, Barnett MJ, Kristal AR, et al.: Genetic variation in myeloperoxidase modifies the association of serum α-tocopherol with aggressive prostate cancer among current smokers. J Nutr 141 (9): 1731-7, 2011.  [PUBMED Abstract]

  18. Clark LC, Combs GF Jr, Turnbull BW, et al.: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276 (24): 1957-63, 1996.  [PUBMED Abstract]

  19. Klein EA: Selenium and vitamin E cancer prevention trial. Ann N Y Acad Sci 1031: 234-41, 2004.  [PUBMED Abstract]

  20. Lippman SM, Klein EA, Goodman PJ, et al.: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301 (1): 39-51, 2009.  [PUBMED Abstract]

  21. Klein EA, Thompson IM Jr, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011.  [PUBMED Abstract]

  22. Kristal AR, Darke AK, Morris JS, et al.: Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J Natl Cancer Inst 106 (3): djt456, 2014.  [PUBMED Abstract]

  23. Lippman SM, Goodman PJ, Klein EA, et al.: Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). J Natl Cancer Inst 97 (2): 94-102, 2005.  [PUBMED Abstract]

  24. Ledesma MC, Jung-Hynes B, Schmit TL, et al.: Selenium and vitamin E for prostate cancer: post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) status. Mol Med 17 (1-2): 134-43, 2011 Jan-Feb.  [PUBMED Abstract]

  25. Dunn BK, Richmond ES, Minasian LM, et al.: A nutrient approach to prostate cancer prevention: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). Nutr Cancer 62 (7): 896-918, 2010.  [PUBMED Abstract]

  26. Select Committee on GRAS Substances (SCOGS) Opinion: alpha-Tocopherols. Silver Spring, Md: Food and Drug Administration, 2013. Available online. Last accessed October 9, 2014. 

Zyflamend



Overview
General Information and History

Zyflamend is a dietary supplement that contains extracts of rosemary (Rosmarinus officinalis L.), turmeric (Curcuma longa L.), ginger (Zingiber officinale Roscoe), holy basil (Ocimum sanctum L.), green tea (Camellia sinensis [L.] Kuntze), hu zhang (Polygonum cuspidatum Siebold & Zucc., a source of resveratrol), Chinese goldthread (Coptis chinensis Franch.), barberry (Berberis vulgaris L.), oregano (Origanum vulgare L.), and Baikal skullcap (Scutellaria baicalensis Georgi). The individual components of Zyflamend have anti-inflammatory and possible anti-carcinogenic properties. For example, results of a 2011 study suggest that Zyflamend may inhibit the growth of melanoma cells.[1]

The extracts in Zyflamend have been shown to have anti-inflammatory effects via inhibition of cyclooxygenase (COX) activity. COXs are enzymes that convert arachidonic acid into prostaglandins, which are thought to play a role in tumor development and metastasis. One COX enzyme, COX-2, is activated during chronic disease states, such as cancer.[2]

The antitumorigenic mechanisms of action of Zyflamend are unknown, but, according to one study, Zyflamend may suppress activation of nuclear factor-kappa B (NF-kappa B) (a nuclear transcription factor involved in tumorigenesis) and NF-kappa B–regulated gene products.[3]

Preclinical/Animal Studies

In vitro studies

In a study reported in 2012, human prostate cancer cells were treated in vitro with Zyflamend. Cells treated with the supplement at concentrations ranging from 0.06 to 0.5 μL /mL exhibited dose-dependent decreases in androgen receptor and prostate-specific antigen (PSA) expression levels, compared with cells treated with the dimethyl sulfoxide vehicle control. Prostate cancer cells that were treated with a combination of Zyflamend (0.06 μL/mL) and bicalutamide (25 μM), an androgen receptor inhibitor, showed reductions in cell growth, PSA expression, and anti-apoptotic protein expression, compared with cells treated with Zyflamend or bicalutamide alone.[4]

Although the individual components of Zyflamend have been shown to influence COX activity, one study examined the effects of the drug on COX-1 and COX-2 expression in prostate cancer cells. The results revealed that Zyflamend, at a concentration of 0.9 μL/mL, inhibited expression of both COX-1 and COX-2; at a concentration of 0.45 μL/mL. The degree of COX-2 inhibition was observed, but the level of COX-1 inhibition was reduced by 50%. At a concentration of 0.1 μL/mL, Zyflamend effectively inhibited growth of prostate cancer cells and increased the level of caspase-3, a pro-apoptotic enzyme. However, a separate experiment indicated that the prostate cancer cells used in the study (LNCaP cells, which are androgen sensitive) did not express high levels of COX-2, suggesting that Zyflamend’s effects on prostate cancer cells may result from a COX-independent mechanism.[2]

The lipoxygenase isozymes 5-LOX and 12-LOX are also proteins associated with inflammation and tumor growth. In a 2007 study, the effects of Zyflamend on 5-LOX and 12-LOX expression were investigated. The findings indicated that 0.25–2 μL/mL Zyflamend produced decreases in 5-LOX and 12-LOX expression in PC3 prostate cancer cells (cells that have high metastatic potential). The supplement also inhibited cell proliferation and induced apoptosis. In addition, Zyflamend treatment resulted in a decrease in Rb phosphorylation (Rb proteins control cell-cycle -related genes). These results indicate that Zyflamend may inhibit prostate cancer cell growth through a variety of mechanisms.[5]

In a 2011 study, human prostate cancer cells were treated with Zyflamend (200 µg /mL). After 48 hours of treatment, a statistically significant reduction in cell growth was observed for Zyflamend-treated cells, compared with control cells (P < .005). In another experiment, prostate cancer cells were treated with insulin-like growth factor -1 (IGF-1; 0–100 ng /mL) alone or in combination with Zyflamend (200 µg/mL). Cells treated with IGF-1 alone exhibited statistically significant, dose-dependent increases in cell proliferation, whereas cells treated with both IGF-1 and Zyflamend showed significant decreases in cell proliferation. Zyflamend was also shown to decrease cellular levels of the IGF-1 receptor and the androgen receptor in prostate cancer cells.[6]

Animal studies

Additional evidence that Zyflamend promotes apoptosis in cancer cells was obtained in laboratory and animal studies reported in 2012.[7] Treatment of human colorectal carcinoma cell lines in vitro with Zyflamend was shown to significantly down regulate expression of anti-apoptotic proteins, up regulate expression of Bax (a pro-apoptotic protein), and increase expression of death receptor 5 (DR5), a receptor important in apoptosis. Moreover, when nude mice with pancreatic cancer cell implants were randomly assigned to receive Zyflamend or a control treatment for 4 weeks, tumor cells from the Zyflamend-treated mice showed significant reductions in anti-apoptotic proteins and significantly increased expression of DR5, compared to tumor cells from control-treated animals.

In a 2011 study, mice were also implanted with pancreatic cancer cells and then treated with gemcitabine and/or Zyflamend. The combination treatment resulted in a significantly greater decrease in tumor growth than did treatment with gemcitabine or Zyflamend alone. Other findings from this study suggest that Zyflamend exerted its effects by sensitizing the pancreatic tumors to gemcitabine through suppression of multiple targets linked to tumorigenesis.[8]

Human Studies

Intervention studies

In one case report, a patient with high-grade prostatic intraepithelial neoplasia (HGPIN) received Zyflamend 3 times daily for 18 months. Zyflamend did not affect this patient's PSA level, but, after 18 months, repeat core biopsies of the prostate did not show PIN or cancer.[9]

In a 2009 phase I study designed to assess safety and toxicity, patients with HGPIN were assigned to take Zyflamend (780 mg) 3 times daily for 18 months, plus combinations of dietary supplements (i.e., probiotic supplement, multivitamin, green and white tea extract, Baikal skullcap, docosahexaenoic acid, holy basil, and turmeric). Zyflamend and the additional dietary supplements were well tolerated by the patients, and no serious adverse events occurred. After 18 months of treatment, 60% of the study subjects had only benign tissue at biopsy; 26.7% had HGPIN in one core; and 13.3% had prostate cancer.[10]

Adverse Effects

Zyflamend was well tolerated in the previously described 2009 clinical study. Mild heartburn was reported in 9 of 23 subjects, but it resolved when the study supplements were taken with food. No serious toxicity or adverse events were reported in the study.[10]

References
  1. Ekmekcioglu S, Chattopadhyay C, Akar U, et al.: Zyflamend mediates therapeutic induction of autophagy to apoptosis in melanoma cells. Nutr Cancer 63 (6): 940-9, 2011.  [PUBMED Abstract]

  2. Bemis DL, Capodice JL, Anastasiadis AG, et al.: Zyflamend, a unique herbal preparation with nonselective COX inhibitory activity, induces apoptosis of prostate cancer cells that lack COX-2 expression. Nutr Cancer 52 (2): 202-12, 2005.  [PUBMED Abstract]

  3. Sandur SK, Ahn KS, Ichikawa H, et al.: Zyflamend, a polyherbal preparation, inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of NF-kappa B activation and NF-kappa B-regulated gene products. Nutr Cancer 57 (1): 78-87, 2007.  [PUBMED Abstract]

  4. Yan J, Xie B, Capodice JL, et al.: Zyflamend inhibits the expression and function of androgen receptor and acts synergistically with bicalutimide to inhibit prostate cancer cell growth. Prostate 72 (3): 244-52, 2012.  [PUBMED Abstract]

  5. Yang P, Cartwright C, Chan D, et al.: Zyflamend-mediated inhibition of human prostate cancer PC3 cell proliferation: effects on 12-LOX and Rb protein phosphorylation. Cancer Biol Ther 6 (2): 228-36, 2007.  [PUBMED Abstract]

  6. Huang EC, Chen G, Baek SJ, et al.: Zyflamend reduces the expression of androgen receptor in a model of castrate-resistant prostate cancer. Nutr Cancer 63 (8): 1287-96, 2011.  [PUBMED Abstract]

  7. Kim JH, Park B, Gupta SC, et al.: Zyflamend sensitizes tumor cells to TRAIL-induced apoptosis through up-regulation of death receptors and down-regulation of survival proteins: role of ROS-dependent CCAAT/enhancer-binding protein-homologous protein pathway. Antioxid Redox Signal 16 (5): 413-27, 2012.  [PUBMED Abstract]

  8. Kunnumakkara AB, Sung B, Ravindran J, et al.: Zyflamend suppresses growth and sensitizes human pancreatic tumors to gemcitabine in an orthotopic mouse model through modulation of multiple targets. Int J Cancer 131 (3): E292-303, 2012.  [PUBMED Abstract]

  9. Rafailov S, Cammack S, Stone BA, et al.: The role of Zyflamend, an herbal anti-inflammatory, as a potential chemopreventive agent against prostate cancer: a case report. Integr Cancer Ther 6 (1): 74-6, 2007.  [PUBMED Abstract]

  10. Capodice JL, Gorroochurn P, Cammack AS, et al.: Zyflamend in men with high-grade prostatic intraepithelial neoplasia: results of a phase I clinical trial. J Soc Integr Oncol 7 (2): 43-51, 2009.  [PUBMED Abstract]

Other Prostate Health Supplements



Overview

Many widely available dietary supplements are marketed to support prostate health. African cherry (Pygeum africanum) and beta-sitosterol are two related supplements that have been studied as potential prostate cancer treatments.

African Cherry/P. africanum

P. africanum is a tree from the Rosaceae family that grows in tropical zones. It is found in a number of African countries including Kenya, Madagascar, Uganda, and Nigeria. Bark from the P. africanum tree was used by African tribes to treat urinary symptoms and gastric pain.[1] In the 18th century, European travelers learned from South African tribes that P. africanum was used to treat bladder discomfort and “old man’s disease” (enlarged prostate).

Since 1969, bark extracts from P. africanum have been available as prescription drugs in Europe and have been widely used to treat benign prostatic hyperplasia.[2,3] The bark contains a number of compounds including saturated and unsaturated fatty acids, phytosterols (e.g., beta-sitosterol), pentacyclic triterpenoids (e.g., oleanolic acid), alcohols, and carbohydrates. The extract is obtained by macerating and solubilizing the bark in an organic solvent. The extract is then purified from the solvent.[1]

Two components of P. africanum bark extracts, atraric acid and N-butylbenzene-sulfonamide, are androgen receptor inhibitors, as indicated by both in vitro [4-6] and animal in vivo [7] studies. This activity is produced by each of these components at concentrations that are significantly lower than the clinically achieved concentration of the antiandrogen flutamide.[8]

Beta-Sitosterol

Beta-sitosterol is a phytochemical found at various concentrations in plants such as P. africanum, saw palmetto, and some legumes. Specifically, it is a type of phytosterol (or plant sterol) and has a similar structure to cholesterol. Phytosterols, including beta-sitosterol, reduce absorption of dietary cholesterol and their potential to protect against cardiovascular disease is under investigation. Mean plasma beta-sitosterol concentration in a small group of healthy male volunteers in Vienna, Austria, was 2.83 μg /mL (approximately 7 μM).[9] Interestingly, however, a rare condition caused by mutations in the adenosine triphosphate -binding cassette (ABC) transporter ABCG5 or ABCG8 genes results in an inherited sterol storage disease with markedly increased serum concentrations of plant sterols such as sitosterol and leads to premature atherosclerosis and large xanthomas.[10]

Research has also suggested that phytosterols may have anticarcinogenic properties, but the exact mechanisms are unknown.[11] Phytosterols may exert antitumor effects by acting on immune and hormonal systems, or by directly targeting cell cycles and inducing apoptosis in tumor cells.[12]

Beta-sitosterol at concentrations around 16 mM has been shown to significantly inhibit growth of PC-3 prostate cancer cells and induce apoptosis.[13,14] Associated with these effects are decreasing levels of cell cycle regulators p21 and p27 in the cancer cells and an increased production of reactive oxygen species.

References
  1. Brackman FG, Edgar A, Coates PM: Pygeum. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 650-5. 

  2. Ishani A, MacDonald R, Nelson D, et al.: Pygeum africanum for the treatment of patients with benign prostatic hyperplasia: a systematic review and quantitative meta-analysis. Am J Med 109 (8): 654-64, 2000.  [PUBMED Abstract]

  3. Levin RM, Das AK: A scientific basis for the therapeutic effects of Pygeum africanum and Serenoa repens. Urol Res 28 (3): 201-9, 2000.  [PUBMED Abstract]

  4. Papaioannou M, Schleich S, Prade I, et al.: The natural compound atraric acid is an antagonist of the human androgen receptor inhibiting cellular invasiveness and prostate cancer cell growth. J Cell Mol Med 13 (8B): 2210-23, 2009.  [PUBMED Abstract]

  5. Papaioannou M, Schleich S, Roell D, et al.: NBBS isolated from Pygeum africanum bark exhibits androgen antagonistic activity, inhibits AR nuclear translocation and prostate cancer cell growth. Invest New Drugs 28 (6): 729-43, 2010.  [PUBMED Abstract]

  6. Schleich S, Papaioannou M, Baniahmad A, et al.: Extracts from Pygeum africanum and other ethnobotanical species with antiandrogenic activity. Planta Med 72 (9): 807-13, 2006.  [PUBMED Abstract]

  7. Shenouda NS, Sakla MS, Newton LG, et al.: Phytosterol Pygeum africanum regulates prostate cancer in vitro and in vivo. Endocrine 31 (1): 72-81, 2007.  [PUBMED Abstract]

  8. Handratta VD, Vasaitis TS, Njar VC, et al.: Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem 48 (8): 2972-84, 2005.  [PUBMED Abstract]

  9. Duchateau G, Cochrane B, Windebank S, et al.: Absolute oral bioavailability and metabolic turnover of β-sitosterol in healthy subjects. Drug Metab Dispos 40 (10): 2026-30, 2012.  [PUBMED Abstract]

  10. Tsubakio-Yamamoto K, Nishida M, Nakagawa-Toyama Y, et al.: Current therapy for patients with sitosterolemia--effect of ezetimibe on plant sterol metabolism. J Atheroscler Thromb 17 (9): 891-900, 2010.  [PUBMED Abstract]

  11. Awad AB, Fink CS: Phytosterols as anticancer dietary components: evidence and mechanism of action. J Nutr 130 (9): 2127-30, 2000.  [PUBMED Abstract]

  12. Bradford PG, Awad AB: Phytosterols as anticancer compounds. Mol Nutr Food Res 51 (2): 161-70, 2007.  [PUBMED Abstract]

  13. Awad AB, Burr AT, Fink CS: Effect of resveratrol and beta-sitosterol in combination on reactive oxygen species and prostaglandin release by PC-3 cells. Prostaglandins Leukot Essent Fatty Acids 72 (3): 219-26, 2005.  [PUBMED Abstract]

  14. Scholtysek C, Krukiewicz AA, Alonso JL, et al.: Characterizing components of the Saw Palmetto Berry Extract (SPBE) on prostate cancer cell growth and traction. Biochem Biophys Res Commun 379 (3): 795-8, 2009.  [PUBMED Abstract]

Changes to This Summary (10/10/2014)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Lycopene

Added text about a 2013 meta-analysis, including four of five cohort studies from a 2004 meta-analysis, two new meta-analyses, and three case-control studies from the previous study plus eight new ones, that reported less convincing evidence for risk reduction; the authors concluded that tomatoes may play a modest role in the prevention of prostate cancer (cited Chen et al. as reference 26).

Soy

Added text about an updated 2013 meta-analysis that confirmed the good safety profiles of isoflavones but indicated no significant differences between treated and control groups for prostate-specific antigen (PSA) levels or sex steroid endpoints (cited van Die et al. as reference 22).

Added text to state that another group conducted a randomized placebo-controlled trial to examine the effect of soy isoflavone capsules on localized prostate cancer in 86 men who took the capsules for up to 6 weeks before prostatectomy; changes in serum-free and total testosterone, PSA, and total cholesterol were not different between the two groups, and the investigators noted that the 12 genes involved in cell cycle control and the 9 genes involved in apoptosis were down regulated in the tumor tissues of the isoflavone-treated men, compared with the controls (cited Hamilton-Reeves et al. as reference 32).

Added text to state that in a 2 X 2 factorial design study that investigated soy protein powder and venlafaxine in 120 androgen-deprived men, neither proved effective alone or in combination in decreasing hot flashes, although the number of vasomotor symptoms decreased significantly in all four arms over the 12-week trial; soy protein, but not venlafaxine, produced statistically significant improvements in emotional and functional subscales on quality-of-life instruments (cited Vitolins et al. as reference 40).

Vitamin D

Added text about a 2014 study that evaluated calcitriol and a less-calcemic vitamin D analog in an aggressive transgenic adenocarcinoma of the mouse prostate model and found that neither vitamin D analog impacted the rate of development of castration-resistant prostate cancer in mice, whether they were treated before or after castration; however, both vitamin D analogs slowed progression of primary tumors in hormone-intact mice but enhanced distant organ metastases after prolonged treatment (cited Ajibade et al. a reference 8). Also added text to state that this preclinical data supports findings of the 2008 retrospective study of an association between serum vitamin D levels and aggressive prostate cancer (cited Ahn et al. as reference 9).

Added text to state that a 2008 retrospective study of 749 men with prostate cancer diagnosed 1 to 8 years after blood draw and 781 matched controls found higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease. Also added text to state that both of these studies were included in a meta-analysis of 21 studies, involving 11,941 cases and 13,870 controls, that found a 17% elevated risk of prostate cancer in men with higher levels of 25(OH)D; one explanation offered for this finding may be a potential detection bias with men from higher socio-economic groups who have higher vitamin D levels and who are more likely to undergo PSA testing, resulting in higher reported incidence rates (cited Xu et al. as reference 17).

Added text to state that serum 25(OH)D levels were obtained from 667 men in Chicago undergoing first prostate biopsy for an elevated PSA or an abnormal digital rectal exam; severe vitamin D deficiency was associated with increased risk of a prostate cancer diagnosis on biopsy among African American men, and severe deficiency was positively associated with higher Gleason score, higher clinical stage, and overall risk category in both white and African American men (cited Murphy et al. as reference 18). Also added text to state that baseline serum 25(OH)D levels obtained in a case-cohort analysis from the Selenium and Vitamin E Cancer Prevention Trial found significantly reduced risks among men who had moderate concentrations compared with men who had lower or higher values (cited Kristal et al. as reference 19).

Vitamin E

Added text about a meta-analysis of nine nested case-control studies, representing approximately 370,000 men from several countries, that also found an inverse relationship between alpha-tocopherol levels and prostate cancer risk but in all the men studied rather than limited to a smoking subset; no association was seen with gamma-tocopherol levels. Also added text to state that the risk of prostate cancer decreased by 21% for every 25 mg/L increase in blood alpha-tocopherol level (cited Cui et al. as reference 11).

This summary is written and maintained by the PDQ Cancer Complementary and Alternative Medicine Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary



Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Complementary and Alternative Medicine Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Prostate Cancer, Nutrition, and Dietary Supplements are:

  • Donald I. Abrams, MD (UCSF Osher Center for Integrative Medicine)
  • Nagi B. Kumar, PhD, RD, FADA (Fellow of the American Dietetic Association)
  • Channing J Paller, MD (Johns Hopkins Hospital)
  • Jeffrey D. White, MD (National Cancer Institute)

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Levels of Evidence

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National Cancer Institute: PDQ® Prostate Cancer, Nutrition, and Dietary Supplements. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/cam/prostatesupplements/healthprofessional. Accessed <MM/DD/YYYY>.

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