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

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Green Tea

Overview
General Information and History
Preclinical/Animal Studies
        In vitro studies
        Animal studies
        Animal Safety Studies
Human Studies
        Epidemiologic studies
        Safety Studies
        Intervention studies
        Current Clinical Trials



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
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