Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)–Health Professional Version

In vitro studies

Prostate cancer cells were treated with bovine milk, almond milk, soy milk, casein, or lactose in a 2011 study. Treatment with bovine milk resulted in growth stimulation of LNCaP prostate cancer cells. Growth of prostate cancer cells was not affected by treatment with soy milk, and treatment with almond milk resulted in growth inhibition.[4]

In vivo studies

One study investigated the effects of dietary calcium on prostate tumor progression in LPB-Tag transgenic mice. The animals consumed low (0.2%) or high (2.0%) calcium diets and were sacrificed at age 5, 7, or 9 weeks. Tumor weight and progression were similar in mice that were fed low- and high-calcium diets.[5]

A 2012 study examined the impact of dietary vitamin D and calcium on prostate cancer growth in athymic mice. The mice were injected with human prostate cancer cells and were randomly assigned to receive specific diets (e.g., high calcium/vitamin D or normal calcium/no vitamin D). The mice that received the normal calcium/vitamin D-deficient diet exhibited significantly greater (P < .05) tumor volumes than did mice that received the other diets.[6]

Epidemiological studies

Several epidemiological studies have found an association between high intakes of calcium, dairy foods, or both, and an increased risk of developing prostate cancer.[7-9] However, others have found only a weak relationship, no relationship, or a negative association between calcium intake and prostate cancer risk.[10-14] A 2022 prospective cohort study examined 28,737 men who belong to the Seventh-day Adventist church. These men had wide ranges of dairy and calcium intake. The study found that a higher intake of dairy foods or other potentially causal factors associated with dairy intake were associated with a higher risk of prostate cancer. This was not true for nondairy sources of calcium. On the basis of these studies, interpretation of the evidence is complicated by the difficulty of separating the effects of dairy products from the effects of calcium. Additionally, earlier epidemiological studies had several limitations. The association between dairy foods, calcium intake, and prostate cancer was limited to evidence from self-reported food frequency questionnaires of nutritional sources of calcium, with a focus on dairy foods.[14-16] Competing risk factors, such as other major nutrients in dairy (i.e., total fats, saturated fats, calories) and concomitant and confounding factors (i.e., age, body mass index, steroid hormones, and other metabolic events in the causal pathway) were not accounted for. Additionally, no objective markers of calcium, such as serum calcium, were obtained from these cohorts. Observational studies overall, however, suggest that high total calcium intake may be associated with increased risk of advanced and metastatic prostate cancer, compared with lower intake of calcium.[11,12,17-19] Another analysis of 886 prostatectomy patients found an increased risk of being diagnosed with more aggressive disease in men with higher calcium intakes.[20] The hazard of disease recurrence after surgical treatment was increased in men with both very low and high calcium intakes. Additional research is needed to clarify the effects of calcium and/or dairy products on prostate cancer risk and to elucidate potential biological mechanisms.

Interventional studies

In a randomized clinical trial published in 2005, 672 men received either 3 g of calcium carbonate (1,200 mg calcium) or placebo daily for 4 years and were followed for 12 years. During the first 6 years of the study, there were significantly fewer prostate cancer cases in the calcium group compared with the placebo group. However, this difference was no longer statistically significant at the 10-year evaluation.[21]

Meta-analyses

A meta-analysis published in 2005 reported that there may be an association between increased risk of prostate cancer and greater consumption of dairy products and calcium.[22]

A 2008 meta-analysis reviewed 45 observational studies and found no evidence of a link between dairy products and risk of prostate cancer.[23] A meta-analysis of cohort studies published between 1996 and 2006 found a positive association between milk and dairy product consumption and risk of prostate cancer.[24]

In a recent review, the U.S. Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews, conducted meta-analyses using Mantel-Haenszel fixed effects models for overall cancer incidence, cardiovascular disease incidence, and all-cause mortality. Vitamin D and/or calcium supplementation showed no overall effect on cancer incidence and mortality, including prostate cancer.[3] In a meta-analysis of the association of calcium without the coadministration of vitamin D, a reduced risk of prostate cancer was observed, although there were only a few events.[25]

In 2007, the World Cancer Research Fund/American Institute for Cancer Research reported that there was probable evidence that diets high in calcium increase the risk of prostate cancer and that there is limited suggestive evidence that milk and dairy products also increase the risk.[26] Since publication, 18 additional studies that evaluated dairy or calcium intake and the risk of prostate cancer have been published. A 2015 meta-analysis of this literature concluded that high intakes of dairy products, milk, low-fat milk, cheese, total dietary calcium, and dairy calcium may increase prostate cancer risk.[27] Supplemental calcium and nondairy calcium were not associated with an increased risk, although supplemental calcium was associated with an increased risk of fatal prostate cancer. The authors suggested that this association needs additional study.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

In vitro studies

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.[8]

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 with radiation alone.[9]

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.[10]

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.[11]

Advances in nanotechnology—nanochemoprevention—may result in more-effective administration of EGCG to men at risk of developing 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.[12] In one 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.[13]

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 proteins, which bind to methylated DNA. These results indicate that green tea polyphenols may have chemopreventive effects via actions on gene-silencing processes.[14]

The results of a 2011 study suggested that green tea polyphenols may exert anticancer effects by inhibiting histone deacetylases (HDACs). 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.[15]

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.[16,17]

Animal studies

Animal models have been used in several studies investigating the effects of green tea on prostate cancer. In one study, TRAMP mice were given access to water or GTC–treated water (0.3% GTC 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 GTCs showed only prostatic intraepithelial neoplasia lesions, suggesting that GTCs may help delay the development of prostate tumors.[18] 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 with vehicle treatment.

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/wk) exhibited less androgen receptor protein expression than did mice that were treated with vehicle.[19]

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).[20] 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.[20] In one study, EGCG treatment (0.06% EGCG in drinking water; this exposure mimics human consumption of 6 cups of green tea/d) 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.[21]

Using the TRAMP mouse model,[22] one study demonstrated that oral infusion of GTP extract at a human-achievable dose (equivalent to 6 cups of green tea/d) 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 (IGF)-1; 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. In another study, 119 male TRAMP mice and 119 C57BL/6J mice were treated orally with one of three doses of Polyphenon E (200, 500, or 1,000 mg/kg/d) in drinking water ad libitum, replicating human-achievable doses. Safety and efficacy assessments were performed at baseline and when mice were 12, 22, and 32 weeks old. Results indicated that the number and size of tumors in treated TRAMP mice were significantly decreased, compared with untreated animals. In untreated 32-week-old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period.[23]

Animal safety studies

In a National Cancer Institute (NCI) Division of Cancer Prevention (DCP)–sponsored, 9-month, oral toxicity study, Polyphenon E was administered (200, 500, or 1,000 mg/kg/d) 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. These studies have revealed some unique dose-limiting lethal liver, gastrointestinal, and renal toxicities. Gross necropsy revealed therapy-induced lesions in the gastrointestinal tracts, livers, kidneys, reproductive organs, and hematopoietic tissues of treated male and female dogs. In the 13-week follow-up study, the no-observed-adverse-effect–level was greater than 600 mg/kg per day of Polyphenon E.[24] When the study was conducted in nonfasted dogs under the same testing conditions and dose levels, the results were unremarkable. Nonspecific toxicity and a tenfold reduction in the maximum tolerated dose in fasted beagle dogs compared with fed beagle dogs were seen using a purified GTC containing less than 77% EGCG.[25] However, in the follow-up NCI DCP–sponsored study, which compared fed dogs with fasted dogs using several Polyphenon E formulations, no deaths occurred, suggesting that fasting may have rendered the target organ systems more vulnerable to the effects of green tea extract.

In a study [23] of several doses of a standardized Polyphenon E targeting TRAMP mice, no liver or other toxicities were observed. Long-term (32 weeks) treatment with Polyphenon E (200, 500, and 1,000 mg/kg/d) was safe and well tolerated, with no evidence of toxicity in C57BL/6J mice. The C57BL/6J mice showed no differences in appearance or behavior, or changes in prostate and body weights after 32 weeks of treatment for all three doses of Polyphenon E. No discernible histopathological changes were observed in the liver, lung, or any prostate lobe of C57BL/6J mice treated with the three different doses of Polyphenon E.[23] Similarly, another preclinical study [26] did not observe liver or other toxicities with standardized EGCG at doses of up to 500 mg EGCG preparation/kg per day.

Epidemiological studies

The relationship between green tea intake and prostate cancer has been examined in several epidemiological studies.

Two meta-analyses examined the consumption of green tea and prostate cancer risk, with one meta-analysis including black tea.[27,28] 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.[27] The inconsistent results reported in these population studies may be attributed to confounding factors that include the following:[29-33]

In Asian countries with a high per capita consumption of green tea, prostate cancer mortality rates are among the lowest in the world,[34] and the risk of prostate cancer appears to be increased among Asian men who abandon their original dietary habits upon migrating to the United States.[34] Overall, findings from population studies suggest that green tea may help protect against prostate cancer in Asian populations.[27,35] 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 GTCs.

Interventional studies

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

In vitro studies

In vitro studies that have examined a link between lycopene and prostate carcinogenesis have suggested several mechanisms by which lycopene might reduce prostate cancer risk. Lycopene is broken down into a number of metabolites that are thought to have various biological effects, including antioxidant capabilities and a role in gap-junction communication.[8]

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 might lower the risk of prostate cancer.[9]

In addition, treating prostate cancer cells with lycopene resulted in a significant decrease in the number of lycopene-treated cells in the 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, reduced prostate cancer cell proliferation and may modulate cell-cycle progression.[10]

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.[11]

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, whereas treating cells with a combination of the PPARγ antagonist and lycopene decreased cell proliferation.[12]

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.[13] 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.[14]

A study examining the effect of lycopene on multiple points along the nuclear factor-kappa B (NF-kappa B) signaling pathways in prostate cell lines demonstrated a 30% to 40% reduction in inhibitor of kappa B (I-kappa B) phosphorylation, NF-kappa B transcriptional activity and a significant reduction in cell growth at the physiologically relevant concentration of 1.25 μM or higher.[15] These results provided evidence that the anticancer properties of lycopene may occur through inhibition of the NF-kappa B signaling pathway, beginning at the early stage of cytoplasmic IKK kinase activity, which then leads to reduced NF-kappa B–responsive gene regulation. Additionally, these effects in the cancer cells were observed at concentrations of lycopene that are relevant and achievable in vivo.

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.[16]

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.[17]

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/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.[18]

Lycopene has also been studied for potential therapeutic effects in xenograft models. 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.[19] In an in vitro study, the investigators demonstrated the effect of lycopene in androgen-independent prostate cancer cell lines.[20] In another study, nude mice were injected with human prostate cancer cells and treated with intraperitoneal injections of docetaxel, lycopene (15 mg/kg/d) 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.[16]

Epidemiological studies

Several epidemiological 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 risk of prostate cancer.[7,9-13] Prospective and case-control studies have shown lycopene to be significantly lower in the serum and tissue of patients with cancer than in controls,[7,16-19,21] while other studies have failed to demonstrate such a connection.[22]

An association between lycopene serum concentration and risk of cancer was also examined in men participating in the Kuopio Ischaemic Heart Disease Risk Factor 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 [RR], 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 (RR, 0.43; 95% CI, 0.23–0.79; P = .007) but not prostate cancer.[23]

A 2015 systematic review and meta-analysis of studies investigating dietary lycopene intake/circulating lycopene levels and prostate cancer risk found that when lycopene intake was higher, the incidence of prostate cancer was reduced (P = .078).[24] Similarly, a higher level of circulating lycopene was associated with lower prostate cancer risk. Likewise, a 2017 systematic review and meta-analysis evaluated lycopene dietary intake and circulating lycopene with prostate cancer risk. An inverse association between high levels of both circulating (RR, 0.88; 95% CI, 0.79–0.98; P = .019) and dietary lycopene (RR, 0.88; 95% CI, 0.78–0.98; P = .017) with prostate cancer risk was noted.[25]

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 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.[26] A follow-up study was conducted that examined serum lycopene and risk of prostate cancer in the same group of PLCO participants. The results suggested no significant difference in serum lycopene concentrations between healthy participants and participants who developed prostate cancer.[27]

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.[28]

At least two studies examined the effect of lycopene blood levels on the risk of high-grade prostate cancer. The first study examined the associations between carotenoid levels and the risk of high-grade prostate cancer, and also considered antioxidant-related genes and tumor instability. This study demonstrated that plasma carotenoids at diagnosis, particularly among men carrying specific somatic variations, were inversely associated with risk of high-grade prostate cancer. Higher lycopene concentrations were associated with less genomic instability among men with low-grade disease, indicating that lycopene may inhibit progression of prostate cancer early in its natural history.[29]

In another study examining whether carotenoid intake and adipose tissue carotenoid levels were inversely associated with prostate cancer aggressiveness, results suggested that diets high in lycopene may protect against aggressive prostate cancer in White American men, and diets high in beta-cryptoxanthin may protect against aggressive prostate cancer in African American men.[30]

One study investigated the correlation between lycopene blood levels and the rate of progression of prostate cancer. This study examined plasma carotenoids and tocopherols in relation to PSA levels among men with biochemical recurrence of prostate cancer. This study indicated that the plasma cis-lutein/zeaxanthin level at 3 months was inversely related to PSA level at 3 months (P = .0008), while alpha-tocopherol (P = .01), beta-cryptoxanthin (P = .01), and all-trans-lycopene (P = .004) levels at 3 months were inversely related to PSA levels at 6 months. Percentage increase in alpha-tocopherol and trans-beta-carotene levels from baseline to month 3 was associated with lower PSA levels at 3 and 6 months. Percentage increase in beta-cryptoxanthin, cis-lutein/zeaxanthin and all-trans-lycopene was associated with lower PSA levels at 6 months only.[31]

A study examined the association of prediagnosis and postdiagnosis dietary lycopene and tomato product intake with prostate-cancer specific mortality in a prospective cohort of men diagnosed with nonmetastatic prostate cancer. No association between serum lycopene, tomato products, and prostate-cancer specific mortality was observed. Among men with high-risk cancers (T3–T4, Gleason score 8–10, or nodal involvement), consistently reporting lycopene intake that was at or above the median was associated with lower prostate-cancer specific mortality.[32]

In a recently reported prospective study of 27,934 U.S. Adventist men who were followed for up to 7.9 years, consumption of canned and cooked tomato-based products (measured as grams for both tomato products and lycopene), was inversely related to the risk of prostate cancer compared with those with zero intake of these foods. Associations of prostate cancer risk with raw tomatoes was not statistically significant. No differences in adjusted competing risk analyses were observed between aggressive and nonaggressive prostate cancers. The study was limited to self-reported food frequency questionnaires for data collection; however, lycopene concentrations were not quantified in this population.[33]

The variability in these epidemiological study results may be related to lycopene source; exposure misclassification; inconsistent measures of intake; differences in absorption; differences in individual lycopene metabolism; 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. Most studies have examined the association of lycopene intake with the risk of all prostate cancers and have not separately considered indolent versus aggressive disease. Given these caveats, results based on epidemiological evidence should be interpreted with caution.

Interventional studies

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

In a phase II, randomized, placebo-controlled trial,[46] 45 men with clinically localized prostate cancer received either 15, 30, or 45 mg of lycopene (Lyc-O-Mato) 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, compared with disease-free controls, and similar to levels observed in previous studies in men with prostate cancer.[52,53] At the 30 mg lycopene dose level, a moderate decrease in mean free testosterone and significant increases in mean plasma estradiol and in serum sex hormone-binding globulin (SHBG) (P = .022) were observed. At the 45 mg/d dose, serum total estradiol increased (P = .006) 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, in which 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.[46]

In a single-arm study of previously untreated men diagnosed with localized prostate cancer, investigators determined whether PSA velocity was altered by a 1-year intervention with lycopene supplementation (10 mg/d). A statistically significant decrease in PSA velocity after lycopene treatment was observed (P = .0007). Analysis of the PSA-doubling time (pretreatment vs. post-treatment) showed a median increase after supplementation for 174 days; however, this was not statistically significant.[47]

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/d). 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.[48]

In a 2004 open-label study, patients with hormone-refractory prostate cancer (HRPC) (N = 20) received lycopene supplements daily (10 mg/d 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.[50] In a phase II study, HRPC patients took lycopene supplements daily (15 mg of lycopene/d) 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.[51]

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/d) for at least 4 months. Only one patient in this study exhibited a decrease in PSA level. Several episodes of gastrointestinal side effects were noted after eating the tomato paste or drinking the tomato juice.[49]

On the basis of the available evidence, early randomized clinical trials with lycopene as a single agent, in tomato products, and in combination with other agents (fish oil supplements, tomato products plus selenium, omega-3 fatty acids, soy isoflavones, grape/pomegranate juice and green/black tea) demonstrates bioavailability in serum and modulation of intermediate biomarkers implicated in prostate carcinogenesis and prostate cancer progression in most studies. Perhaps, future clinical trials should include longer duration of consistent lycopene exposure, while accounting for variations in individual absorption of carotenoids and heterogeneity of high-risk (HGPIN, atypical small acinar proliferation) and prostate cancer patient populations (indolent vs. aggressive prostate cancer or androgen-dependent vs. androgen-independent prostate cancer).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

In vitro studies

In a 2007 study, pectins were investigated for their anticancer properties. Prostate cancer cells were treated with three different pectins; CP, Pectasol (PeS, a dietary supplement containing MCP), 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 one 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]

Interventional studies

In a 2007 pilot study, patients with advanced solid tumors (various types of cancers, 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/d) for 12 months. Following treatment, 7 of 10 patients had a statistically significant (P ≤ .05) increase in PSADT.[10]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

In vitro 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.

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 (0.3 mg/mouse/dose). Ellagic acid (EA) was detected in the prostate following intraperitoneal, but not oral, administration of pomegranate extract (0.8 mg/mouse/dose).[8]

Treating human prostate cancer cells with individual components of the pomegranate fruit has been shown to inhibit cell growth.[9-12] In one study, dihydrotestosterone-stimulated LNCaP cells were treated with 13 pomegranate compounds at various concentrations (0–100 µM).[10] 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 (a major constituent of pomegranate seeds) being the strongest inducer of apoptosis. Additionally, findings from this study suggested that punicic acid may activate apoptosis by a caspase-dependent pathway.[10]

Pomegranate extracts have also been shown to inhibit the proliferation of human prostate cancer cells in vitro.[11,13,14] In one study, three prostate cancer cell lines (LNCaP, LNCaP-AR, and DU-145) were treated with pomegranate polyphenols (punicalagin [PA] or 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.[11] In a second 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.[14]

The enzyme cytochrome P450 (CYP1B1) has been implicated in cancer development and progression. As a result, CYP1B1 inhibitors may be effective anticarcinogenic 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.[15]

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.[13]

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 suggested that PJ may be beneficial in slowing down or preventing cancer cell metastasis. [16]

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.[14] In other studies, treatment with a POMx resulted in decreased tumor volumes in SCID mice that had been injected with prostate cancer cells.[8,17]

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 before 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).[9]

In a study 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 age 20 weeks, whereas just 30% and 20% of the mice that received 0.1% and 0.2% PJ, respectively, developed tumors. By age 34 weeks, 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 with the water-fed mice.[18]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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 (MSeA) 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]

Animal studies

A 2012 study investigated whether various forms of selenium (i.e., SeMet and selenium-enriched yeast [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 tissue 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 with 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 transgenic adenocarcinoma of the mouse prostate (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 with 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] One study suggested that MSeA may inhibit cell growth and increase apoptosis by inactivating PKC isoenzymes.[22]

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 European Prospective Investigation into Cancer and Nutrition (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 a 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 (relative risk, 1.35; 95% confidence interval [CI], 0.99–1.84).[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 SEPP 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 a patient had for the gene encoding the enzyme MnSOD. For men with the alanine-alanine (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 valine (V) allele.[25]

An analysis of 4,459 men in the Health Professionals Follow-Up Study who were initially diagnosed with prostate cancer found that selenium supplementation of 140 μg or more per day after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality. The authors recommended caution in the use of selenium supplements among men with prostate cancer. Risk of prostate cancer mortality rose at all levels of selenium consumption. Men who consumed 1 to 24 μg/day, 25 to 139 μg/day, and 140 μg/day or more of supplemental selenium had a 1.18-fold (95% CI, 0.73–1.91), 1.33-fold (95% CI, 0.77–2.30), and 2.60-fold (95% CI, 1.44–4.70) increased prostate cancer mortality risk compared with nonusers, respectively (P_trend = .001). The authors reported no statistically significant association between selenium supplement use and biochemical recurrence, cardiovascular disease mortality, or overall mortality.[30]

In summary, these epidemiological studies present a conflicting picture. Some studies showed that higher selenium levels were associated with a decreased risk of prostate cancer; others showed a correlation between higher selenium levels and more aggressive prostate cancer. Genetic differences in the SEPP gene may explain the different responses to selenium.

Interventional studies

Interventional studies have examined the efficacy of selenium in preventing and treating prostate cancer.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

In vitro studies

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 epidermal growth factor receptor (EGFR) and insulin like growth factor-1 receptor (IGF-1R) in TRAMP mice, suggesting that down regulation of these proteins may be one mechanism by which genistein exerts chemopreventive effects.[16] In one 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, compared with 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/d or 400 mg genistein/kg body weight/d) 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/d), mixed isoflavones (50 mg/kg body weight/d; 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]

In the treatment of prostate cancer, bone health is a common concern in the setting of hormone deprivation therapy, which is associated with bone loss. Because of increased beta versus alpha estrogen receptor binding, soy-derived compounds are thought to be protective of bone. Animal studies have shown that genistein and daidzein can prevent or reduce bone loss in a manner similar to synthetic estrogen. Both isoflavones may modulate bone remodeling by targeting and regulating gene expression and may inhibit calcium urine excretion, which also helps to maintain bone density.[21,22]

Epidemiological studies

In 2018, 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) was significantly associated with a decrease in the risk of prostate cancer. Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with a reduced risk of prostate cancer.[26] However, these data from population studies must be interpreted with caution as the studies relied on self-reported data obtained using varying forms of dietary data collection instruments with recall bias, in addition to numerous forms of individual or multiple isoflavones, soy supplements, and soy foods. Additionally, these studies failed to account for other confounding genetic or behavioral variables that may affect the risk of prostate cancer.

Prevention studies

Too few randomized placebo-controlled trials have been completed to evaluate the effect of isoflavones or soy in preventing prostate cancer progression (see Table 3). The studies targeted men with negative prostate biopsies and elevated serum prostate-specific antigen (PSA) (2.5–10 mcg/mL at baseline). The duration of intervention was between 6 months [15] and 1 year [27,28], with varying formulations of isoflavones derived from soy [15,27] and red clover.[28] In a single trial that showed no significant changes in serum PSA after intervention with isoflavones, a reduction in prostate cancer progression at 1 year in a subgroup of men older than 65 years was demonstrated. Other than mild to moderate adverse events, no treatment-related toxicities were observed in all three trials.

Treatment of prostate cancer

Clinical trials evaluating isoflavones, soy supplements, and soy products (see Table 4 and Table 5) for treating localized prostate cancer before radical prostatectomy have used window-of-opportunity trial designs (from biopsy to prostatectomy). These trials have primarily focused on evaluating serum and tissue biomarkers implicated in prostate cancer progression, bioavailability in plasma and prostate tissue, and toxicity at various doses. The trials are small in size and of short duration. They are useful for informing the design of well-powered larger clinical trials in the future, but they provide inadequate data to inform clinical practice.

Isoflavones and soy products for biochemical recurrence after treatment

Other studies have examined the role of isoflavones and soy products in prostate cancer patients with biochemical recurrence after treatment. However, these early-phase studies have not demonstrated any significant changes in serum PSA or PSA-doubling time, [40-43] with one study suggesting modulation of systemic soluble and cellular biomarkers consistent with limiting inflammation and suppression of myeloid-derived suppressor cells [43] (see Table 6).

Management of androgen deprivation therapy side-effects

ADT 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, changes in cognition, and metabolic syndrome. Three studies have examined men undergoing ADT who were randomly assigned to receive a placebo or an isoflavone supplement (soy protein powder mixed with beverages; isoflavones, 160 mg/d) for 12 weeks. Two studies assessed ADT side effects. Neither study found an improvement in side effects following isoflavone treatment, compared with placebo.[44,45]

The third randomized placebo-controlled trial assessed changes in PSA level and biomarkers of energy metabolism (e.g., blood glucose level) and inflammation (e.g., blood interleukin-6 level). In this study of men undergoing ADT, participants were randomly assigned to receive high-dose isoflavone supplements (providing 160 mg/d 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).[38]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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 (VDBP) transports vitamin D in the bloodstream. Studies have shown that one of its products, VDBP-macrophage activating factor (VDBP-maf), may have antiangiogenic and antitumor activities. One study examined the effects of VDBP-maf on prostate cancer cells. Treating prostate cancer cells with VDBP-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 VDBP-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 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]

Androgen metabolism in prostate cancer cells may be altered by 1,25-dihydroxyvitamin D (1,25(OH)₂D), providing an additional antitumor mechanism. Vitamin D compounds activate enzymes involved in cholesterol and steroid hormone metabolism. This may reduce intracellular testosterone levels in prostate cell lines and decrease the availability of pro-survival androgenic steroids.[6]

Vitamin D has also been combined with radiation in an in vitro study. In this 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.[7]

In vivo studies

Tumor progression was compared in two murine models of prostate cancer. In vitamin D receptor–knockout animals, the 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.[8]

In a 2011 study, nude mice were fed a control diet or a diet deficient in vitamin D and then injected with prostate cancer cells into bone marrow or 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.[9]

A 2014 study evaluated calcitriol and a less-calcemic vitamin D analogue in an aggressive transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Neither vitamin D analogue 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).[10] This preclinical data supports findings of the 2008 retrospective study [11] of an association between serum vitamin D levels and aggressive prostate cancer. For more information about this study, see the Human Studies section.

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.[12] A subsequent study corroborated these findings, showing that combining calcitriol and cryoablation resulted in more cell death than cryotherapy alone.[13]

In vitro and in vivo studies have shown that vitamin D compounds potentiate the cytotoxicity of many anticancer agents, including docetaxel.[6] The effect is most pronounced when vitamin D compounds are administered before or simultaneously with the cytotoxic agents.

Epidemiological studies

The relationship between vitamin D and prostate cancer has been examined in numerous epidemiological studies with mixed results. A meta-analysis published in 2011 reviewed 25 studies that examined the link between prostate cancer incidence and indicators of vitamin D intake or sufficiency. No association was found between dietary vitamin D or circulating concentrations of vitamin D and risk of prostate cancer.[14]

Interventional studies

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.[40]

Calcitriol (1,25-dihydroxy vitamin D), 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. This treatment was effective in decreasing the rate of rising PSA levels in study participants, suggesting it may slow disease progression.[41] 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.[42]

In a 2018 randomized controlled trial, men aged 50 years or older and women aged 55 years or older received vitamin D3 (cholecalciferol) and omega-3 fatty acid supplements for the prevention of cancer and cardiovascular disease. The vitamin D supplement did not result in a lower incidence of any cancer, including prostate cancer, or cardiac disease compared with a placebo.[43]

A systematic review and meta-analysis of 16 before-after studies and 6 randomized controlled studies evaluated the effect of vitamin D supplementation on PSA change, PSA response proportion, mortality, and adverse effects. The analysis of controlled clinical trials found no significant difference between vitamin D supplementation and the placebo groups for PSA change from baseline (weighted mean difference, -1.66 ng/mL; 95% CI, -0.69 to 0.36; P = .543), PSA response proportion (RP) (RP, 1.18; 95% CI, 0.97–1.45; P = .104), and mortality rate (RR, 1.05; 95% CI, 0.81–1.36; P = .713). Single-arm trials revealed that vitamin D supplementation had a modest effect on PSA response proportion. Nineteen percent of enrolled patients had at least a 50% reduction in PSA levels by the end of treatment (95% CI, 7%–31%; P = .002). The authors believed that the evidence from these studies did not show important benefits from vitamin D supplementation and thus such supplementation should not be recommended as part of treatment.[44]

A post hoc analysis was conducted on data from two randomized controlled trials. Patients with castration-resistant prostate cancer received the combination of a statin and vitamin D with abiraterone (AA). The analysis reported that one study (COU-AA-301) found that the use of AA with a statin and vitamin D reduced the risk of death by 38% (P = .0007), while AA alone was associated with a decrease in the risk of death by 10% (P = .025). The second study (COU-AA-302) compared AA plus a statin and vitamin D with prednisone alone and found that the use of AA plus a statin and vitamin D was associated with a reduced risk of death by 26% (P = .0054).[45]

Symptom management

A small group of patients (N = 59) who underwent androgen deprivation therapy (ADT) were randomly assigned to receive high-dose vitamin D (600 IU/day plus 50,000 IU/week), low-dose vitamin D (600 IU/day), or a placebo for 24 weeks.[46] Muscle mass was measured using bioelectric impedance analysis (BIA), and strength was measured before and after supplementation. Muscle mass improved with high-dose vitamin D3 supplementation, but strength did not. No other measures of cancer outcomes were reported.

Vitamin D toxicity

In most cases, symptoms of vitamin D toxicity are caused by hypercalcemia, but limited evidence suggests high concentrations of vitamin D may also be expressed in various organs, including the following:

Symptoms of toxicity may be observed at an intake of 10,000 to 50,000 IU per day over a period of many years. Hypercalcemia results from the vitamin D–dependent increase in intestinal absorption of calcium, leading to rapid increases in blood calcium levels. Side effects include loss of the urinary concentrating mechanism of the kidney tubule (resulting in polyuria and polydipsia), decrease in growth factor receptor, hypercalciuria, and the metastatic calcification of soft tissues. The central nervous system may also be affected, resulting in severe depression and anorexia.[47]

A systematic review of the interactions and pharmacokinetics of vitamin D and drugs used for the treatment of cancer was published.[48] Based on the review, 26 articles met the inclusion criteria. Calcitriol was the most commonly administered form of vitamin D, and adults with prostate cancer and solid tumors were the most well-represented populations in this systematic review. Hypercalcemia (at a dose of 74 μg/wk [3,000 IU]; 125 μg/wk [5,000 IU] with the addition of dexamethasone) was the most frequently reported side effect.

Hypophosphatemia was also observed in two studies [49,50] that administered vitamin D in conjunction with docetaxel in men with prostate cancer. The authors concluded that no adverse effects were experienced beyond what was expected from high-dose calcitriol supplementation and was denoted as having a low risk of interaction. Some chemotherapeutic regimens appear to reduce serum 25(OH)-D3 and/or 1,25-D3.

A number of studies evaluated the safety and efficacy of high-dose calcitriol in conjunction with chemotherapy drugs in men with androgen-independent prostate cancer, hormone-refractory prostate cancer, and metastatic castration-resistant prostate cancer.[50-52] In the studies that used docetaxel plus calcitriol for men with androgen-independent prostate cancer, no increased toxicity was observed when compared with docetaxel alone.

In men with hormone-refractory prostate cancer, one study examined the activity and tolerability of weekly high-dose calcitriol (32 μg/wk [1,300 IU]) with docetaxel in patients who had previously received docetaxel treatment.[49] Calcitriol was given orally in three divided doses, and docetaxel was given intravenously (30 mg/m2) with dexamethasone (8 mg) orally 12 hours before, at the time of, and 12 hours after docetaxel administration. Most of the side effects were expected toxicities related to the chemotherapy. Grade 2 hypercalcemia was observed in one patient. Administration of calcitriol was discontinued until hypercalcemia resolved. Supplementation was restarted after 2 weeks. In another patient, persistent grade 3 fatigue was observed, and treatment of calcitriol was discontinued as docetaxel was reduced.

Phase I trials

Phase I studies have looked at the maximum tolerated dose (MTD) of weekly intravenous and oral calcitriol in conjunction with various chemotherapy drugs for cancer treatment. One study examined the MTD of calcitriol in conjunction with gefitinib at 250 mg/day (oral chemotherapy used to treat lung cancer) in 32 patients with advanced solid tumors that were metastatic or unresectable.[53] At doses up to 74 μg (3,000 IU) per week, no dose-limiting toxicities were observed. Grade 2 hypercalcemia was observed in two of four patients receiving 96 μg per week (3,900 IU) of calcitriol and was denoted nontolerable. No significant bone marrow suppression was observed at any dose. A dose of 74 μg (3,000 IU) per week was denoted as the MTD. The study suggests no major interaction between calcitriol and gefitinib.

A second phase I study examined the MTD and pharmacokinetics of calcitriol when administered with paclitaxel over the course of 6 weeks.[54] Thirty-six patients (heterogenous diagnoses) were enrolled in the trial and received escalating doses of oral calcitriol starting at 4 μg (160 IU) for 3 consecutive days, increasing to 38 μg (1,520 IU) with an 80-mg/m2 infusion of paclitaxel given weekly. Results demonstrate that very high doses of calcitriol can be safely administered with paclitaxel. There was no dose-limiting toxicity in the trial, and at a dose of 38 μg/wk, no clinically significant hypercalcemia occurred. However, it is important to note that participants were administered from 8 to 76 capsules of calcitriol with no report of adherence to the prescribed dose of calcitriol.

Epidemiological studies

The National Institutes of Health-American Association of Retired Persons (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 who 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 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.

The North Carolina-Louisiana Prostate Cancer Project investigated racial and geographic differences in prostate cancer aggressiveness.[12] The effects of food intake of tocopherols, vitamin E supplementation, and adipose tissue biomarkers of tocopherol were studied. In 1,023 African American men and 1,079 White men with incident prostate cancer, inverse associations were observed between dietary sources of tocopherol and prostate cancer aggressiveness that were statistically significant in White men but not in African American men.

Interventional studies

The Physicians’ Health Study II investigated whether vitamin C or vitamin E prevents prostate cancer and other cancers in men. Participants were randomly assigned to receive vitamin E (synthetic alpha-tocopherol, 400 IU qod) and/or vitamin C (synthetic ascorbic acid, 500 mg/d) 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.[13]

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.[14] A long follow-up study of participants in the ATBC Study was conducted. Baseline serum alpha-tocopherol levels and dietary intake of vitamin E was 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.[15] 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.[16] 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.[17] Findings from 28 years of follow-up of the cohort confirmed the lack of association between serum alpha-tocopherol levels and prostate cancer risk.[18] However, high alpha-tocopherol concentration was associated with a decreased risk of prostate cancer among participants in the trial who were supplemented with alpha-tocopherol (fifth quintile vs. first quintile; hazard ratio [HR], 0.79; 95% CI, 0.64–0.99).

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. There was an inverse relationship between prostate cancer risk and serum alpha-tocopherol levels in certain genotypes.[19]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Overview

General information and history

Zyflamend is a dietary supplement that contains CO₂ and hydroalcoholic extracts of the following herbs, combined and suspended in olive oil:

The individual components of Zyflamend have anti-inflammatory and possible anticarcinogenic properties. For example, results of a 2011 study suggest that Zyflamend may inhibit the growth of melanoma cells.[4]

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.[5]

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.[6]

Several companies distribute Zyflamend as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of Zyflamend as a treatment for cancer or any other medical condition.

Preclinical/animal studies

Human studies

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.[14]