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Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®): Complementary and alternative medicine - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Prostate Cancer, Nutrition, and Dietary Supplements
This complementary and alternative medicine (CAM) information summary provides an overview of the use of various foods and dietary supplements for reducing the risk of developing prostate cancer or for treating prostate cancer. This summary includes the history of research on the following six different foods or dietary supplements, reviews of laboratory and animal studies, and results of clinical trials.
- Green tea.
- Lycopene.
- Modified citrus pectin.
- Pomegranate.
- Soy.
- Zyflamend.
Each type of dietary supplement or food will have a dedicated section in the summary, and new topics will be added over time.
Prostate cancer is the most common noncutaneous cancer affecting men in the United States. From 2004 to 2008, the median age of diagnosis of prostate cancer was 67, and the incidence rate was 156 cases per 100,000 men per year.[1]
Many studies suggest that CAM use is common among prostate cancer patients, and the use of vitamins, supplements, and specific foods is frequently reported by these patients. For example, the Prostate CAncer Therapy Selection (PCATS) study was a prospective that study investigated men's decision-making processes about treatment following a diagnosis of local stage prostate cancer. As part of this study, patients completed surveys regarding CAM use, and more than half of the respondents reported using one or more CAM therapies, with mind-body modalities and biologically based treatments being the most commonly used.[2]
International studies have reported similar findings. A Swedish study published in 2011 found that, overall, participants with prostate cancer were more likely to have used supplements than were healthy population-based control subjects. Supplement use was even more common among patients with the healthiest dietary patterns (e.g., high consumption of fatty fish and vegetables).[3] In a Canadian study, CAM use was reported among 39% of recently diagnosed prostate cancer patients, and the most commonly used forms of CAM were herbals, vitamins, and minerals. Within those categories, saw palmetto, vitamin E, and selenium were the most popular. The two most popular reasons for choosing CAM were to boost the immune system and to prevent recurrence.[4] According to another Canadian study, approximately 30% of survey respondents with prostate cancer reported using CAM treatments. In that study, vitamin E, saw palmetto, and lycopene were most commonly used.[5] A British study published in 2008 indicated that 25% of prostate cancer patients used CAM, with the most frequently reported interventions being low-fat diets, vitamins, and lycopene. The majority of CAM users in this study cited improving quality of life and boosting the immune system as the main reasons they used CAM.[6]
Vitamin and supplement use has also been documented in men at risk of developing prostate cancer. One study examined vitamin and supplement use in men with a family history of prostate cancer. At the time of the survey, almost 60% of the men were using vitamins or supplements. One third of the men were using vitamins and supplements that were specifically marketed for prostate health or chemoprevention (e.g., selenium, green tea, and saw palmetto).[7] A 2004 study examined herbal and vitamin supplement use in men who attended a prostate cancer screening clinic. Men who attended the screening clinic completed questionnaires about supplement use. Of the respondents, analysis revealed that a reported 70% used multivitamins, and 21% used herbal supplements.[8]
A meta-analysis published in 2008 reviewed studies that reported vitamin and mineral supplement use among cancer survivors. The results showed that, among prostate cancer survivors, vitamin or mineral use ranged from 26% to 35%.[9]
Although many prostate cancer patients use CAM treatments, they do not all disclose their CAM use to treating physicians. According to results from the PCATS study, 43% of patients discussed their CAM use with a healthcare professional.[2] In two separate studies, 58% of respondents told their doctors about their CAM usage.[4,6]
How do prostate cancer patients decide whether to use CAM or not? A qualitative study published in 2005 described results from interviews with prostate cancer patients who were CAM users or nonusers. The study identified differences in thinking patterns between the two groups and suggested that no specific theme led patients to CAM, rather a combination of ideas directed them. For example, the perception of CAM being harmless was associated with the belief that conventional medicine resulted in many negative side effects.[10] Results of a 2003 qualitative study suggest that decision making by prostate cancer patients about CAM treatments depends on both fixed (e.g., medical history) and flexible (e.g., a need to feel in control) decision factors.[11]
Green Tea
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, the 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.
Safety Animal 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 1000 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.[28,29,30,31,32] 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.[34,35,36,37] 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.[27,38,39,40] 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.[41,42,43] 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
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.
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 green tea 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.
This section contains the following key information:
- Lycopene is a carotenoid, a natural pigment made by plants and various fruits and vegetables, including tomatoes, apricot, guava, and watermelon.
- Lycopene's absorption is improved with concurrent dietary fat intake.
- Lycopene inhibits androgen receptor expression in prostate cancer cells in vitro and, along with some of its metabolites, reduces prostate cancer cell proliferation and may modulate cell-cycle progression.
- Lycopene may also affect the insulin-like growth factor intracellular pathway in prostate cancer cells.
- Results from several in vitro and animal studies have indicated that lycopene may have chemopreventive effects for cancers of the prostate, skin, breast, lung, and liver; however, human trials have been inconsistent in their findings.
- Clinical trials utilizing lycopene in prostate cancer patients with various different clinical presentations (e.g., early stage, prostate-specific antigen (PSA) relapse, advanced disease) have yielded inconsistent results.
- The U.S. Food and Drug Administration (FDA) has accepted the determination by various companies that their lycopene-containing products meet the FDA's requirements for the designation of Generally Recognized as Safe (GRAS). In clinical trials involving prostate cancer patients, doses ranging from 10 to 120 mg/d have been well tolerated, with only occasional mild-to-moderate gastrointestinal toxicities.
General Information and History
Lycopene is a carotenoid, a natural pigment made by plants, which helps to protect plants from stress,[1] and it also transfers light energy during photosynthesis.[2] Lycopene is found in a number of fruits and vegetables, including apricots, guava, and watermelon, but the majority of lycopene consumed in the United States is from tomato-based products.[1] The bioavailability of lycopene is greater in processed tomato products, such as tomato paste and tomato puree, than it is in raw tomatoes.[3] When ingested, lycopene is broken down into a number of metabolites and is thought to have various biological functions, including antioxidant capabilities and a role in gap-junction communication.[4]
There is evidence that dietary fat may help increase the absorption of carotenoids, including lycopene. In one experiment, healthy volunteers consumed mixed-vegetable salads with nonfat, low-fat, or full-fat salad dressing. Analysis of blood samples indicated that eating full-fat salad dressing led to more carotenoid absorption than eating low-fat or nonfat dressing.[5] Results of a randomized study published in 2005 revealed that cooking diced tomatoes with olive oil significantly increased lycopene absorption compared to cooking tomatoes without olive oil.[6] According to one study,[7] there was no difference in plasma lycopene levels following consumption of tomatoes mixed with olive oil or tomatoes mixed with sunflower oil, suggesting that absorption of lycopene may not be dependent on the type of oil used. However, this same study found that combining olive oil, but not sunflower oil, with tomatoes resulted in greater plasma antioxidant activity.
Lycopene has been investigated for its role in chronic diseases, including cardiovascular disease and cancer. Numerous epidemiological studies suggest that lycopene may help prevent cardiovascular disease, although some interventional studies have shown mixed results.[3] Lycopene may protect against cardiovascular disease by decreasing cholesterol synthesis and increasing the degradation of low-density lipoproteins.[8] A number of in vitro and in vivo studies suggest that lycopene may also be protective against cancers of the skin, breast, lung, and liver.[9] However, epidemiological studies reported to date have yielded inconsistent findings regarding lycopene's potential in reducing cancer risk. The few human intervention trials have been small and generally focused on intermediate endpoints and thus have not been definitive.[2,10]
In 2004, the Food and Drug Administration (FDA) received two petitions for qualified health claims regarding tomatoes, lycopene, and reduced cancer risk. In a 2007 review, the FDA concluded there was not enough evidence to support a claim that lycopene helps reduce cancer risk. The FDA found there was no evidence of a link between tomato consumption and lung, colorectal, breast, cervical, or endometrial cancers, and there was limited evidence for an association between tomato consumption and reduced risks of prostate, ovarian, gastric, and pancreatic cancers.[11]
Preclinical/Animal Studies
In vitro studies
Many in vitro studies have been conducted examining a link between lycopene and prostate cancer.
Treating normal human prostate epithelial cells with lycopene resulted in dose-dependent growth inhibition, indicating that inhibition of prostate cell proliferation may be one way lycopene may lower the risk of prostate cancer.[12]
In addition, treating prostate cancer cells with lycopene resulted in a significant decrease in the number of lycopene-treated cells in S phase of the cell cycle, suggesting that lycopene may lower cell proliferation by altering cell-cycle progression. Moreover, apo-12'-lycopenal, a lycopene metabolite, also reduced prostate cancer cell proliferation and may also modulate cell-cycle progression.[13]
Some studies have suggested that cancer cells have altered cholesterol-biosynthesis pathways. Treating prostate cancer cells with lycopene resulted in dose-dependent decreases in 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (the rate-limiting enzyme in cholesterol synthesis), total cholesterol, and cell growth and an increase in apoptosis. However, adding mevalonate prevented the growth-inhibitory effects of lycopene, indicating that the mevalonate pathway may be important to the anti-cancer activity of lycopene.[14] Lycopene may also affect cholesterol levels in prostate cancer cells by activating the peroxisome proliferator-activated receptor gamma (PPARγ)-liver X receptor alpha (LXRα)-ABCA1 pathway, which leads to decreased cholesterol levels and may ultimately result in decreased cell proliferation. ABCA1 mediates cholesterol efflux, and PPARγ has been shown to inhibit the growth and differentiation of prostate cancer cells. In one study, treating prostate cancer cells with lycopene resulted in increased expression of PPARγ, LXRα, and ABCA1 as well as lower total cholesterol. In addition, when the cells were treated with a PPARγ antagonist, cell proliferation increased while treating cells with a combination of the PPARγ antagonist and lycopene decreased cell proliferation.[15]
Adding lycopene to medium containing the LNCaP human prostate adenocarcinoma cell line resulted in decreased DNA synthesis and inhibition of androgen-receptor gene-element activity and expression.[16]
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 more cell growth in four of five cell types examined than treatment with docetaxel alone. The findings suggest that the mechanism for these effects may involve the insulin-like growth factor-1 receptor (IGF-1R) pathway.[17]
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 to control mice than mice supplemented with tomato paste, suggesting that lycopene beadlets may provide greater chemopreventive effects than tomato paste.[18]
Ketosamines are carbohydrate derivatives formed when food is dehydrated. In one study, FruHis (a ketosamine in dehydrated tomatoes) combined with lycopene resulted in greater growth inhibition of implanted rat prostate cancer cells than did lycopene or FruHis alone. In addition, in a N-methyl-N-nitrosourea (NMU)/testosterone-induced prostate carcinogenesis model, rats fed a tomato paste and FruHis diet had longer survival times than rats fed only with tomato paste or tomato powder.[19]
Lycopene has also been studied for potential therapeutic effects in xenograft studies. In one study, athymic nude mice were injected with human androgen-independent prostate cancer cells and were treated with either lycopene (4 mg/kg body weight or 16 mg/kg body weight) or beta-carotene (16 mg/kg body weight). Supplementing mice with lycopene or beta carotene resulted in decreased tumor growth.[20] In an in vitro study, the investigators demonstrated the effect of lycopene in androgen-independent prostate cancer cell lines.[21] In another study, nude mice were injected with human prostate cancer cells and treated with intraperitoneal injections of docetaxel, lycopene (15 mg/kg per day) administered via gavage, or a combination of both. Mice exhibited longer survival times and smaller tumors when treated with a combination of docetaxel and lycopene than when they were treated with docetaxel alone.[17]
Human Studies
Epidemiologic studies
Several epidemiologic studies have assessed potential associations between lycopene intake and prostate cancer incidence.
Epidemiological studies have demonstrated that populations with high intake of dietary lycopene have lower risks of prostate cancer.[11,12,13,14,15,16] Prospective and case control studies have shown lycopene to be significantly lower in the serum and tissue of patients with cancer than in controls,[11,17,18,19,20] 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 (KIHD) study in Finland. In this prospective cohort study, an inverse association between lycopene levels and overall cancer risk was observed, suggesting that higher concentrations of lycopene may help lower cancer risk overall. Men with the highest levels of serum lycopene had a 45% lower risk of cancer than did men with the lowest levels of lycopene (risk ratio, 0.55; 95% CI, 0.34–0.89; P = .015). However, when the analysis was restricted to specific cancer types, an association was observed for other cancers (risk ratio, 0.43; 95% confidence interval [CI], 0.23–0.79; P = .007) but not prostate cancer.[23]
A 2004 meta-analysis of studies investigating tomato intake and prostate cancer risk found a small positive effect of tomato products on risk reduction. Among men who consumed high amounts of raw tomato products, the relative risk (RR) of prostate cancer was 0.89 (95% CI, 0.80–1.00), compared with men who ate the least amount of raw tomatoes. For men who consumed the most cooked tomato products, the RR was 0.81 (95% CI, 0.71–0.92).[24]
The National Cancer Institute's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial is an ongoing, prospective study that has been a source of subjects for investigations of an association between lycopene intake and prostate cancer risk. A 2006 study examined lycopene and tomato product intakes and prostate cancer risk among PLCO participants who had been followed up for an average of 4.2 years. Lycopene and tomato product intakes were assessed via Food Frequency Questionnaires. Overall, no association was found between dietary intake of lycopene or tomato products and the risk of prostate cancer. However, among men with a family history of prostate cancer, increased lycopene consumption was associated with decreased prostate cancer risk.[25] A follow-up study was conducted that examined serum lycopene and risk of prostate cancer in the same group of PLCO participants. The results suggest that there was no significant difference in serum lycopene concentrations between healthy participants and participants who developed prostate cancer.[26]
The variability in these epidemiological study results may be related to lycopene source; exposure misclassification; lack of a dose response; and confounding lifestyle factors, such as obesity, use of tobacco and alcohol, other dietary differences, varying standardization of quantities and compositions of lycopene, geographical location, and genetic risk factors. Given these caveats, results based on epidemiological evidence should be interpreted with caution.
Intervention studies
A number of clinical studies have been conducted investigating lycopene as a chemopreventive agent and as a potential treatment for prostate cancer.
Healthy males participated in a crossover design study that attempted to differentiate the effects of tomatoes from those of lycopene. After study entry, the participants consumed their usual diet for 1 week followed by a 2-week washout period on a lycopene-free diet. Next, they were randomly assigned to consume either yellow tomato paste (0 mg/day lycopene) (Group 1) or red tomato paste (16 mg/day lycopene) (Group 2) for 1 week as part of their regular diets, followed by a second 2-week washout period. Then, the participants in Group 1 crossed over to red tomato paste, and the participants in Group 2 crossed over to yellow tomato paste for 1 week as part of their regular diets, followed by a third 2-week washout period. Finally, the participants in Group 1 took a capsule of lycopene (16 mg/day) and the participants in Group 2 took a placebo daily for 1 week. Circulating lycopene levels increased only after consumption of red tomato paste and the lycopene capsules. Changes in serum prostate-specific antigen (PSA) level, antioxidant status, and insulin-like growth factor-1 level were not modified by the consumption of tomato paste and lycopene. When prostate cancer cells were treated in vitro with sera collected from participants after red tomato paste consumption, insulin-like growth factor binding protein-3 (IGFBP-3) and the ratio of Bax to Bcl2 were up regulated, and cyclin-D1, p53, and Nrf-2 were down regulated compared to expression levels obtained using sera taken after the first washout period. Intermediate gene expression changes were observed using sera collected from participants after yellow tomato paste consumption. These findings suggest that lycopene may not be the only factor responsible for the protective effects of tomatoes.[27]
In another study, the effect of tomato sauce on apoptosis in benign prostate hyperplasia (BPH) tissue and carcinomas was examined. Patients who were scheduled for prostatectomy were given tomato sauce pasta entrees (30 mg/day of lycopene) to eat daily for 3 weeks before surgery. Patients scheduled for surgery who did not receive the tomato sauce pasta entrees served as control subjects. Those who consumed the tomato sauce pasta entrees exhibited significantly decreased serum PSA levels and increased apoptotic cell death in BPH tissue and carcinomas.[28]
In a third study, patients with high-grade prostate intraepithelial neoplasia (HGPIN) received 4 mg of lycopene twice a day or no lycopene supplementation for 2 years. A greater decrease in serum PSA levels was observed in those treated with lycopene supplements, compared with those who did not take the supplementation. During follow-up, adenocarcinomas were diagnosed more often in patients who had not received the supplements than in patients who had received lycopene (6/20 vs. 2/20). These findings suggest that lycopene may be effective in preventing HGPIN from progressing to prostate cancer.[29] In another study, men at high risk of prostate cancer (e.g., HGPIN) were randomly assigned to receive a daily multivitamin (that did not contain lycopene) or the same multivitamin and a lycopene supplement (30 mg/day) for 4 months. No statistically-significant difference was observed in serum PSA levels between the two treatment groups. These findings suggest that, although lycopene supplements may be safe to take for at least 4 months, they may not affect PSA levels.[30]
Other studies have examined the potential therapeutic effect of lycopene-containing products in patients with prostate cancer. The effects of lycopene supplementation on prostate tissue and prostate cancer biomarkers were investigated in patients with localized prostate cancer in a 2002 pilot study. Patients received lycopene supplements (30mg/day) or no intervention twice daily for 3 weeks prior to radical prostatectomy. Patients who received the lycopene supplements had smaller tumors and lower serum PSA levels than patients who did not receive the supplements. These results suggest that lycopene may be beneficial in prostate cancer treatment.[31] A 2006 study investigated whether lycopene supplements (10 mg/day) would affect PSA velocity in patients with localized prostate cancer over the course of 1 year of treatment. There was a statistically significant decrease in PSA velocity following lycopene treatment as well as a large, but not statistically significant, increase in PSA doubling time.[32]
In a phase II, randomized, placebo-controlled trial,[33] 45 men with clinically localized prostate cancer received either 15, 30 or 45 mg of lycopene or no supplement from time of biopsy to prostatectomy (30 days). Plasma lycopene increased from baseline to the end of treatment in all treatment groups, with the greatest increase observed in the 45 mg lycopene-supplemented arm. No toxicity was reported. Overall, men with prostate cancer had lower baseline levels of plasma lycopene, similar to levels observed in previous studies in men with prostate cancer. At the 30 mg lycopene dose level, a moderate decrease in mean free testosterone and a significant increase in mean plasma estradiol was observed (24.90 [+/−7.94] to 32.30 [+/−7.93]; P = .02). In addition, significant increase in serum SHBG (39.31 [+/−16.04] to 45.67 [+/−19.83]; P = .022) and total estradiol (27.54 pmol/L [SD 7.82] to 37.64 pmol/L [SD12.65]; P = .006) was observed in the 45 mg/day lycopene-supplemented arm, with no significant change in serum testosterone. However, serum testosterone and SHBG levels in the control group remained unchanged. The mean difference between groups who received the lycopene supplementation demonstrated a lower percentage of cells expressing Ki-67, compared with the control group. Notably, 75% of subjects in the 30 mg lycopene-supplemented arm had a decrease in the percentage of cells expressing Ki-67, compared with the subjects in the control group, where 100% of the subjects observed an increase. These changes were not statistically significant, compared with the changes in the control arm for this sample size and duration of intervention. Although antioxidant properties of lycopene have been hypothesized to be primarily responsible for its beneficial effects, this study suggests that other mechanisms mediated by steroid hormones may also be involved.[33]
In one study, prostate cancer patients (N = 36) who had biochemical relapse following radiation therapy or surgery received lycopene supplements twice daily for 1 year. There were six cohorts in the study, each receiving a different dose of lycopene (15, 30, 45, 60, 90, or 120 mg/day). Serum PSA levels did not respond to lycopene treatment. Plasma lycopene levels rose and appeared to plateau by 3 months for all doses. The results indicate that, although lycopene may be safe and well tolerated, it did not alter serum PSA levels in biochemically relapsed prostate cancer patients.[34]
In a 2004 open-label study, patients with hormone-refractory prostate cancer (HRPC) (N = 20) received lycopene supplements daily (10 mg/day of lycopene) for 3 months. Of the study's participants, 50% had PSA levels that remained stable, 15% showed biochemical progression, 30% showed a partial response, and one patient (5% of the total sample) exhibited a complete response after treatment. [35] In a phase II study, HRPC patients took lycopene supplements daily (15 mg of lycopene/day) for 6 months. By the end of the study, serum PSA levels had almost doubled in 12 of the 17 patients, and 5 of 17 patients had achieved PSA stabilization. Although this was a small study without a control group, the results suggest that lycopene may not be beneficial for patients with advanced prostate cancer.[36]
In another study, 46 patients with androgen-independent prostate cancer consumed either tomato paste or tomato juice daily (both preparations provided 30 mg of lycopene/day) for at least 4 months. Only one patient in this study exhibited a decrease in PSA level, suggesting that lycopene may not be effective therapy for patients with androgen-independent prostate cancer. A number of participants experienced gastrointestinal side effects after eating the tomato paste or drinking the tomato juice.[37]
In one 2011 study that explored the effects of lycopene and fish oil supplements on gene expression, men with low-risk prostate cancer were randomly assigned to receive lycopene (30 mg of lycopene/day), fish oil (3 g of fish oil capsules/day), or a placebo daily for 90 days. Gene expression analysis showed no statistically significant differential expression of individual genes associated with the consumption of fish oil or lycopene supplements. However, pathway analysis revealed that an oxidative stress response pathway was significantly modulated following lycopene or fish oil supplement use compared with placebo (fish oil: P = .01, lycopene: P = .001).[38]
Current Clinical Trials
Check NCI's list of cancer clinical trials for CAM clinical trials on lycopene for prostate cancer that are actively enrolling patients.
General information about clinical trials is also available from the NCI Web site.
Adverse Effects
Lycopene has been well tolerated in a number of clinical trials involving prostate cancer patients.[27,29,30,32,35] When adverse effects occurred, they tended to present as gastrointestinal symptoms[37] and, in one study, the symptoms resolved when lycopene was taken with meals.[36] Another study reported that one participant withdrew because of diarrhea.[34]
The U.S. Food and Drug Administration (FDA) has accepted the determination by various companies that their lycopene-containing products meet the FDA's requirements for the designation of Generally Recognized as Safe (GRAS).[39]
Modified Citrus Pectin
This section contains the following key information:
- Citrus pectin is a complex polysaccharide found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature.
- Preclinical research suggests that modified citrus pectin (MCP) may have effects on cancer growth and metastasis through multiple potential mechanisms.
- Very limited clinical research has been done with a couple of citrus pectin-containing products. For prostate cancer patients, the results suggest some potential clinical benefits with relatively minor and infrequent adverse events.
General Information and History
Pectin is a complex polysaccharide contained in the primary cell walls of terrestrial plants. The word 'pectin' comes from the Greek word for congealed or curdled. Plant pectin is used in food processing as a gelling agent and also in the formulation of oral and topical medicines as a stabilizer and nonbiodegradable matrix to support controlled drug delivery.[1] Citrus pectin is found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature.[2] Modification results in shorter molecules that dissolve better in water and are more readily absorbed by the body than are complex, longer chain citrus pectins.[3] One of the molecular targets of MCP is galectin-3, a protein found on the surface and within mammalian cells that is involved in many cellular processes, including cell adhesion, cell activation and chemoattraction, cell growth and differentiation, the cell cycle, and apoptosis; MCP inhibits galectin-3 activity.[2]
Some research suggests that MCP may be protective against various types of cancer, including colon, lung, and prostate cancer. MCP may exert its anticancer effects by interfering with tumor cell metastasis or by inducing apoptosis.[4]
MCP was also shown to activate natural killer cells in leukemic cell cultures, suggesting it may be able to stimulate the immune system.[5]
Preclinical Studies/Animal Studies
In vitro studies
In a 2007 study, pectins were investigated for their anticancer properties. Prostate cancer cells were treated with three different pectins; citrus pectin (CP), Pectasol (PeS, a dietary supplement containing modified citrus pectin), and fractionated pectin powder (FPP). FPP induced apoptosis to a much greater degree than did CP and PeS. Further analysis revealed that treating prostate cancer cells with heated CP resulted in levels of apoptosis similar to those following treatment with FPP. This suggests that specific structural features of pectin may be responsible for its ability to induce apoptosis in prostate cancer cells.[4]
In a 2010 study, prostate cancer cells were treated with PeS or PectaSol-C, the only two MCPs previously used in human trials. The researchers postulated that, because it has a lower molecular weight, PectaSol-C may have better bioavailability than PeS. Both types of MCP were tested at a concentration of 1 mg/mL and both were effective in inhibiting cell growth and inducing apoptosis through inhibition of the MAPK/ERK signaling pathway and activation of the enzyme caspase-3.[6]
In another study, the role of galectin-3, a multifunctional endogenous lectin, in cisplatin -treated prostate cancer cells was examined. Prostate cancer cells that expressed galectin-3 were found to be resistant to the apoptotic effects of cisplatin. However, cells that did not express galectin-3 (via silencing RNA knockdown of galectin-3 expression or treatment with MCP) were susceptible to cisplatin-induced apoptosis. These findings suggest that galectin-3 expression may play a role in prostate cancer cell chemoresistance and that the efficacy of cisplatin treatment in prostate cancer may be improved by inhibiting galectin-3.[7]
Animal studies
Only a few studies have been reported on the effects of MCP in animals bearing implanted cancers and only one involving prostate cancer.[8,9] The prostate cancer study examined the effects of MCP on the metastasis of prostate cancer cells injected into rats. In the study, rats were given 0.0%, 0.01%, 0.1%, or 1.0% MCP (wt/vol) in their drinking water beginning 4 days after cancer cell injection. The analysis revealed that treatment with 0.1% and 1.0% MCP resulted in statistically significant reductions in lung metastases but did not affect primary tumor growth.[9]
Human Studies
Intervention studies
In a 2007 pilot study, patients with advanced solid tumors (various types of cancers were represented, including prostate cancer) received MCP (5 g MCP powder dissolved in water) 3 times a day for at least 8 weeks. Following treatment, improvements were reported in some measures of quality of life, including physical functioning, global health status, fatigue, pain, and insomnia. In addition, 22.5% of participants had stable disease after 8 weeks of MCP treatment, and 12.3% of participants had disease stabilization lasting more than 24 weeks.[3]
The effect of MCP on prostate-specific antigen (PSA) doubling time (PSADT) was investigated in a 2003 study. Prostate cancer patients with rising PSA levels received six PeS capsules 3 times a day (totaling 14.4 g of MCP powder daily) for 12 months. Following treatment, 7 of 10 patients had a statistically significant (P ≤ .05) increase in PSADT.[10]
Current Clinical Trials
Check NCI's list of cancer clinical trials for CAM clinical trials on modified citrus pectin for prostate cancer that are actively enrolling patients.
General information about clinical trials is also available from the NCI Web site.
Adverse Effects
In one prospective pilot study, MCP was well tolerated by the majority of treated patients, with the most commonly reported side effects being pruritus, dyspepsia, and flatulence.[3] In another study, no serious side effects from MCP were reported, although three patients withdrew from the study due to abdominal cramps and diarrhea that improved once treatment was halted.[10]
This section contains the following key information:
- The pomegranate (Punica granatum L.) is native to Asia and cultivated widely throughout world.
- Various components of the pomegranate fruit contain bioactive compounds, including catechin phenolics, related flavonoids, and anthocyanins, some of which have antioxidant activity.
- Pomegranate juice and extract, as well as some of their bioactive components, inhibit the proliferation of various prostate cancer cell lines in vitro and induce apoptotic cell death in a dose-dependent manner.
- Cytochrome P450 enzyme inhibition and effects on insulin-like growth factor binding protein -3 (IGFBP-3) have been identified as being involved in the in vitro anticancer activity.
- Studies in rodent models of prostate cancer have shown that ingestion of pomegranate juice can decrease the rate of development, growth, and spread of prostate cancer.
- The only fully reported clinical trial of the use of pomegranate juice in men with prostate cancer showed that, on average, study participants who drank the juice had an increase in their prostate-specific antigen (PSA) doubling time.
- No serious adverse effects have been reported in clinical trials of pomegranate juice administration (8 oz per day for up to 33 months).
General Information and History
The pomegranate (Punica granatum L.) is a member of the Punicaceae family native to Asia (from Iran to northern India) and cultivated throughout the Mediterranean, Southeast Asia, East Indies, Africa, and the United States.[1] The history of the pomegranate goes back centuries—the fruit is considered sacred by many religions and has been used for medicinal purposes since ancient times.[2] The fruit is comprised of peel (pericarp), seeds, and aril (outer layer surrounding the seeds). The peel makes up 50% of the fruit and contains a number of bioactive compounds, including phenolics, flavonoids, and ellagitannins, and minerals such as potassium, magnesium, and sodium. Arils are mainly composed of water and also contain phenolics and flavonoids. Anthocyanins, which are flavonoid present in arils, are responsible for the fruit's and its juice's red color.[3] The majority of antioxidant activity comes from ellagitannins.[4]
Research studies suggest that pomegranates have beneficial effects on a number of health conditions, including cardiovascular disease,[5] and may also have positive effects on oral or dental health.[6]
Preclinical Studies/Animal Studies
Research studies in the laboratory have examined the effects of pomegranate on many prostate cancer cell lines and in rodent models of the disease.
In vitro studies
Ellagitannins (the main polyphenols in pomegranate juice) are hydrolyzed to ellagic acid, and then to urolithin A (UA) derivatives. According to a tissue distribution experiment in wild-type mice, the prostate gland rapidly takes up high concentrations of UA after oral or intraperitoneal administration (0.3mg/mouse/dose). Ellagic acid was detected in the prostate following intraperitoneal, but not oral, administration of pomegranate extract (0.8mg/mouse/dose).[7]
Treating human prostate cancer cells with individual components of the pomegranate fruit has been shown to inhibit cell growth.[8,9,10,11] In one study, dihydrotestosterone -stimulated LNCaP cells were treated with 13 pomegranate compounds at various concentrations (0-100 µM).[9] Four of the 13 compounds, epigallocatechin gallate (EGCG), delphinidin chloride, kaempferol, and punicic acid, exhibited an ability to inhibit cell growth in a dose-dependent manner. Treating cells with EGCG, kaempferol, and punicic acid further resulted in apoptosis, with punicic acid (the primary constituent of pomegranate seeds) being the strongest inducer of apoptosis. Additionally, findings from this study suggest that punicic acid may activate apoptosis by a caspase-dependent pathway.[9]
Pomegranate extracts have also been shown to inhibit the proliferation of human prostate cancer cells in vitro.[10,12,13] In one study, three prostate cancer cell lines (LNCaP, LNCaP-AR, and DU-145) were treated with pomegranate polyphenols [punicalagin (PA) or ellagic acid (EA)], a pomegranate extract (POMx, which contains EA and PA), or pomegranate juice (PJ, which contains PA, EA, and anthocyanins) in concentrations ranging from 3.125 to 50 µg/mL (standardized to PA content). All four treatments resulted in statistically significant increases in apoptosis and dose-dependent decreases in cell proliferation in the three cell lines. However, PJ and POMx were stronger inhibitors of cell growth than were PA and EA. In this study, the effects of PA, EA, POMx, and PJ on the expression of androgen -synthesizing enzyme genes and the androgen receptor were also measured. Although statistically significant decreases in gene expression occurred in LNCaP cells following treatment with POMx and in DU-145 cells following treatment with EA and POMx, significant decreases in gene expression and androgen receptor occurred in LNCaP-AR cells following all of the treatments.[10] In another study, treating PC3 cells (human prostate cancer cells with a high metastatic potential) with POMx (10-100 µg/mL) resulted in cell growth inhibition and apoptosis, both in a dose-dependent manner. Treatment of CWR22Rv1 cells (prostate cancer cells that express the androgen receptor and secrete PSA) with POMx (10-100 µg/mL concentrations of pomegranate fruit extract) led to the inhibition of cell growth, a dose-dependent decrease in androgen receptor protein expression, and dose-dependent reductions in PSA protein levels.[13]
The enzyme cytochrome P450 (CYP1B1) has been implicated in cancer development and progression. As a result, CYP1B1 inhibitors may be effective anti-carcinogenic targets. In a study reported in 2009, the effects of pomegranate metabolites on CYP1B1 activation and expression in CWR22Rv1 prostate cancer cells were examined. In this study, urolithins A and B inhibited CYP1B1 expression and activity.[14]
In addition, the insulin-like growth factor (IGF) system has been implicated in prostate cancer. A study reported in 2010 examined the effects of a POMx on the IGF system. Treating LAPC4 prostate cancer cells with POMx (10 µg/mL concentration of pomegranate extract prepared from skin and arils minus seeds) resulted in cell growth inhibition and apoptosis, but treating the cells with both reagents led to larger effects on growth inhibition and apoptosis. However, these substances may have induced apoptosis by different mechanisms. Other findings suggested that POMx treatment reduced mTOR phosphorylation at Ser2448 and Ser2481, whereas IGFBP-3 increased phosphorylation at those sites. In addition, CWR22Rv1 cells treated with POMx (1 and 10 µg/mL) exhibited a dose-dependent reduction in IGF1 mRNA levels, but treatment with IGFBP-3 or IGF-1 did not alter levels of IGF1; these results suggest that one way POMx decreases prostate cancer cell survival is by inhibiting IGF1 expression.[12]
In a study reported in 2011, human hormone -independent prostate cancer cells (DU145 and PC3 cell lines) were treated with 1% or 5% PJ for times ranging from 12 to 72 hours. The results showed that treatment with PJ increased adhesion and decreased the migration of prostate cancer cells. Molecular analyses revealed that PJ increased the expression of cell-adhesion related genes and inhibited the expression of genes involved in cytoskeletal function and cellular migration. These findings suggest that PJ may be beneficial in slowing down or preventing cancer cell metastasis.[15]
Animal studies
The effects of pomegranate on prostate cancer have been examined using a number of rodent models of the disease. In one study, athymic nude mice were injected with tumor-forming cells. Following inoculation, animals were randomly assigned to receive normal drinking water or PJ (0.1% or 0.2% POMx in drinking water, which resulted in an intake corresponding to 250 or 500 mL of PJ per day for an average adult human). Small, solid tumors appeared earlier in mice drinking normal water only than in mice drinking PJ (8 days vs. 11-14 days). Moreover, tumor growth rates were significantly reduced in mice drinking PJ compared with mice drinking normal water only. Animals drinking PJ also exhibited significant reductions in serum PSA levels compared with animals drinking normal water only.[13] In other studies, treatment with a POMx resulted in decreased tumor volumes in SCID mice that had been injected with prostate cancer cells.[7,16]
Similarly, when nude mice were injected with pomegranate seed oil (2 µg/g body weight), pomegranate pericarp (peel) polyphenols (2 µg/g body weight), or saline 5 to 10 minutes prior to being implanted with solid prostate cancer tumors, mice injected with the pomegranate extracts had significantly smaller tumor volumes compared with the mice injected with saline (P < .001).[8]
In another study, which was reported in 2011, 6-week-old transgenic adenocarcinoma of the mouse prostate (TRAMP) mice received normal drinking water or PJ (0.1% or 0.2% POMx in drinking water) for 28 weeks. The results showed that 100% of the mice that received water only developed tumors by 20 weeks of age, whereas just 30% and 20% of the mice that received 0.1% and 0.2% PJ, respectively, developed tumors. By 34 weeks of age, 90% of the water-fed mice exhibited metastases to distant organs whereas only 20% of the mice that received pomegranate juice showed metastasis. The PJ-supplemented mice exhibited significantly increased life spans compared to the water-fed mice.[17]
Human Studies
In a study reported in 2006, researchers observed the effects of PJ on PSA values in prostate cancer patients (N = 48) who had rising PSA levels following treatment with surgery or radiation therapy. The study participants drank 8 ounces of PJ daily (570 mg/day total polyphenol gallic acid equivalents) for up to 33 months. Drinking PJ was associated with statistically significant increases in PSA doubling time (PSADT). After 33 months of follow-up, the median PSADT increased from 11.5 months to 28.7 months (P < .001). In addition, LNCaP cells were treated in vitro with the subjects' serum before and after the PJ intervention. Results of the in vitro experiments showed a decrease in cell growth and an increase in apoptosis following PJ treatment.[18]
A phase II study evaluated 1-g and 3-g doses of pomegranate extract in 104 men with rising PSA values following initial therapy for localized prostate cancer.[19] The study reported that pomegranate extract was associated with a greater than 6-month increase in PSA doubling time in both treatment arms, without adverse effects.
Current Clinical Trials
Check NCI's list of cancer clinical trials for CAM clinical trials on pomegranate-extract pill for prostate cancer, pomegranate juice for prostate cancer, and pomegranate liquid extract for prostate cancer that are actively enrolling patients.
General information about clinical trials is also available from the NCI Web site.
Adverse Effects
In a study of prostate cancer patients reported in 2006, the PJ intervention was well tolerated and no serious adverse effects were observed.[18]
In a pilot study reported in 2007, the safety of PJ in patients with erectile dysfunction was examined. No serious adverse effects were observed during this study, and no participant dropped out due to adverse side effects. In the analysis of the results, no statistical comparisons were made of the adverse side effects observed in the intervention arm and the placebo arm.[20]
This section contains the following key information:
- Soy foods (e.g., soy milk, miso, tofu, and soy flour) contain phytochemicals that may have health benefits and, among these, soy isoflavones have been the focus of most of the research.
- Soy isoflavones are phytoestrogens. The major isoflavones in soybeans are genistein (the most abundant), daidzein, and glycitein.
- Genistein affects components of multiple growth and proliferation -related pathways in prostate cancer cells, including the COX-2 /prostaglandin, epidermal growth factor (EGF), and insulin-like growth factor (IGF) pathways.
- Some preclinical studies have indicated that the combined effect of multiple isoflavones may be greater than that of a single isoflavone.
- Some animal studies have demonstrated prostate cancer prevention effects with soy and genistein; however, other animal studies have yielded conflicting results regarding beneficial effects of genistein on prostate cancer metastasis.
- Epidemiologic studies have generally found high consumption of nonfermented soy foods to be associated with a decreased risk of prostate cancer.
- Limited human prevention studies have been conducted, and, so far, they have not yielded consistent or definitive findings.
- Treatment trials of various doses and preparations of soy isoflavones in men with prostate cancer have yielded varying results but have generally failed to demonstrate significant effects on prostate-specific antigen (PSA) levels.
- A few clinical trials of soy protein or whole soy products have provided preliminary evidence of the ability of these products to lower PSA levels in men with prostate cancer.
- Soy products are generally well tolerated in patients with prostate cancer. In clinical trials, the most commonly reported side effects were mild gastrointestinal symptoms.
General Information & History
Although records of soy use in China date back to the eleventh century BC, it was not until the 18th century that the plant reached Europe and the United States. The soybean is an incredibly versatile plant: it can be processed into a variety of products including soy milk, miso, tofu, soy flour, and soy oil.[1]
Soy foods contain a number of phytochemicals that may have health benefits but isoflavones have garnered the most attention. Among the isoflavones found in soybeans, genistein is the most abundant and may have the most biological activity.[2] Other isoflavones found in soy include daidzein and glycitein.[3] Isoflavones help soybeans survive in times of stress and have antioxidant, antimicrobial, and antifungal properties.[4]
Isoflavones are quickly taken up by the gut and can be detected in plasma as soon as 30 minutes after the consumption of soy products. Studies suggest that maximum levels of isoflavone plasma concentration may be achieved by 6 hours following soy product consumption.[5] Isoflavones are phytoestrogens (they bind to estrogen receptors) with a greater binding affinity for estrogen receptor beta than for estrogen receptor alpha.[6]
Some studies suggest that soy may have health benefits, including decreasing risk of cardiovascular disease and cancer. A link between isoflavones and cancer was discovered in 1987 when it was shown that genistein inhibited a protein tyrosine kinase that is often overexpressed in cancer cells.[7] Subsequently, genistein was found to inhibit multiple protein tyrosine kinases relevant to cancer cell proliferation.[8] In addition, numerous studies have shown that prostate cancer incidence is very low in Asian countries, where diets tend to be high in soy.[9]
Preclinical/Animal Studies
In vitro studies
Individual isoflavones
A number of laboratory studies have examined ways in which soy components affect prostate cancer cells. In one study, human prostate cancer cells and normal prostate epithelial cells were treated with either an ethanol vehicle (carrier) or isoflavones. Treatment with genistein decreased COX-2 mRNA and protein levels in cancer cells and normal epithelial cells more than did treatment with the vehicle. In addition, cells treated with genistein exhibited reduced secretion of prostaglandin E2 (PGE2) and reduced mRNA levels of the prostaglandin receptors EP4 and FP, suggesting that genistein may exert chemopreventive effects by inhibiting the synthesis of prostaglandins, which promote inflammation.[10] In another study, human prostate cancer cells were treated with genistein or daidzein. The isoflavones were shown to down regulate growth factors involved in angiogenesis (e.g., EGF and insulin-like growth factor 1 [IGF1]) and the interleukin -8 gene, which is associated with cancer progression. These findings suggest that genistein and daidzein may have chemopreventive properties.[11]
Combinations of isoflavones
Some experiments have been conducted comparing effects of individual isoflavones with isoflavone combinations on prostate cancer cells. In one such study, human prostate cancer cells were treated with a soy extract (containing genistin, daidzin, and glycitin), genistein, or daidzein. The soy extract induced cell cycle arrest and apoptosis in prostate cancer cells to a greater degree than did treatment with the individual isoflavones. Genistein and daidzein activated apoptosis in noncancerous benign prostatic hyperplasia (BPH) cells, but the soy extract had no effect on those cells. These findings suggest that products containing a combination of active compounds (e.g., "whole foods") may be more effective in preventing cancer than individual compounds.[12] Similarly, in another study, prostate cancer cells were treated with genistein, biochanin A, quercetin, doublets of those compounds (e.g., genistein + quercetin), or with all three compounds. All of the treatments resulted in decreased cell proliferation, but the greatest reductions occurred using the combination of genistein, biochanin A, and quercetin. The triple combination treatment induced more apoptosis in prostate cancer cells than did individual or doublet compound treatments. These results indicate that combining phytoestrogens may increase the effectiveness of the individual compounds.[13]
At least one study has examined the combined effect of soy isoflavones and curcumin. Human prostate cancer cells were treated with isoflavones, curcumin, or a combination of the two. Curcumin and isoflavones in combination were more effective in lowering PSA levels and expression of the androgen receptor than were curcumin or the isoflavones individually.[14]
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 to TRAMP mice fed a control diet. The genistein-supplemented diet also reduced levels of ERK-1 and ERK-2 (proteins important in stimulating cell proliferation) as well as the growth factor receptors EGFR and IGF-1R in TRAMP mice, suggesting that down regulation of these proteins may be one mechanism by which genistein exerts chemopreventive effects.[15] In another study, following the appearance of spontaneous prostatic intraepithelial neoplasia lesions, TRAMP mice were fed control diets or diets supplemented with genistein (250 or 1000 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.[16] In a study reported in 2008, athymic mice were implanted with human prostate cancer cells and fed a control or genistein-supplemented diet (100 or 250 mg genistein/kg chow). Mice that were fed genistein exhibited less cancer cell metastasis, but no change in primary tumor volume, than did mice fed a control diet. Furthermore, other data suggested that genistein inhibits metastasis by impairing cancer cell detachment.[17] In contrast, in a study reported in 2011, there were more metastases in secondary organs in genistein-treated mice than in vehicle-treated mice. In this latter study, mice were implanted with human prostate cancer xenografts and treated daily with genistein dissolved in peanut oil (80 mg genistein/kg body weight/day or 400 mg genistein/kg body weight/day) or peanut oil vehicle by gavage. In addition, there was a reduction in tumor cell apoptosis in the genistein-treated mice compared with the vehicle-treated mice. These findings suggest that genistein may stimulate metastasis in an animal model of advanced prostate cancer.[18]
Radiation therapy is commonly used in prostate cancer, but, despite this treatment, disease recurrence is common. Therefore, combining radiation with additional therapies may provide longer-lasting results. In one study, human prostate cancer cells were treated with soy isoflavones and/or radiation. Cells that were treated with both isoflavones and radiation exhibited greater decreases in cell survival and greater expression of proapoptotic molecules than cells treated with isoflavones or radiation only. Nude mice were implanted with prostate cancer cells and treated by gavage with genistein (21.5 mg/kg body weight/day), mixed isoflavones (50 mg/kg body weight/day; contained 43% genistein, 21% daidzein, and 2% glycitein) and/or radiation. Mixed isoflavones were more effective than genistein in inhibiting prostate tumor growth, and combining isoflavones with radiation resulted in the largest inhibition of tumor growth. In addition, mice given soy isoflavones in combination with radiation did not exhibit lymph node metastasis, which was seen previously in other experiments combining genistein with radiation. These preclinical findings suggest that mixed isoflavones may increase the efficacy of radiation therapy for prostate cancer.[19]
Human Studies
Numerous clinical studies have been conducted examining the impact of soy use on indicators of the effectiveness of prostate cancer prevention or treatment approaches. These studies have included a wide range of participants (from healthy control subjects to prostate cancer patients at various stages of the disease) and have used a number of different interventions such as soy supplements, beverages, and breads.
Epidemiologic studies
In 2009, a meta-analysis of studies that investigated soy food consumption and risk of prostate cancer was reported. The results of this meta-analysis suggested that high consumption of nonfermented soy foods (e.g., tofu and soybean milk) may significantly decrease the risk of prostate cancer. No association was found between high consumption of fermented soy foods (e.g., miso) and prostate cancer risk.[20] In another study, urinary concentrations of phytoestrogens were assessed in healthy Jamaican men and men newly diagnosed with prostate cancer. There were no differences in urinary concentrations of the isoflavones genistein and daidzein between healthy men and prostate cancer patients. Men who produced equol (a metabolite of daidzein) were at a lower risk of prostate cancer than men who were non-producers.[21]
Prevention studies
In one study, Japanese men who had undergone prostate biopsy, but who did not have cancer, were randomly assigned to receive a supplement containing soy isoflavones (40 mg; comprised of 66% daidzein, 24% glycitin, and 10% genistin) and curcumin (100 mg) or a placebo for 6 months. Overall, there were no differences in PSA levels between the placebo and the treatment groups. However, when subjects were subdivided according to baseline PSA level, patients with a higher baseline PSA level (PSA ≥10 ng/mL) who received supplements exhibited statistically significantly larger decreases in PSA than did patients in the placebo group (P = .02).[14]
Although soy is a standard part of many Asian diets, it is less common in Western diets. Therefore, feasibility studies were undertaken to investigate whether Western participants would adhere to soy-supplementation interventions. In one study, healthy men were randomly assigned to consume a high-soy (two daily soy servings) or low-soy (usual diet) diet for 3 months. Following a 1-month washout period, the men crossed over to the other treatment. Reductions approaching statistical significance were seen in PSA levels following the high-soy diet. These findings suggest that this type of soy intervention study is feasible (i.e., the participants complied with dietary instructions) and that soy may be a potential chemopreventive agent.[22]
In another study, men at risk of prostate cancer or with low-grade prostate cancer received one of three types of protein isolate (soy protein, alcohol-washed soy protein [a common method of producing soy protein concentrate, but results in some loss of isoflavones], or milk protein) for 6 months. The isoflavone content of the interventions was 107±5.0 mg/day for soy protein isolate (containing 53% genistein, 35% daidzein, and 11% glycitein), <6±0.7 mg/day for alcohol-washed soy protein (containing 57% genistein, 20% daidzein, and 23% glycitein), and 0 mg/day for milk protein. Soy protein consumption did not alter prostate tissue biomarkers, alcohol-washed soy protein exerted mixed effects, and less prostate cancer was detected after 6 months in men who had consumed soy proteins compared with men who consumed milk protein.[23]
Other plants also contain some of the same isoflavones found in soy. In one study, patients with elevated PSA levels but negative prostate biopsy specimens received a daily isoflavone preparation extracted from red clover (60 mg/day; contained the isoflavones genistein, daidzein, formononetin, and biochanin A) and were followed up for 1 year. Following 12 months of treatment, there was a significant reduction in PSA levels (P = .019) and a nonsignificant decrease in prostate volume (P = .097). In addition, the isoflavone intervention was well tolerated by the patients and did not cause side effects.[24]
Treatment of prostate cancer
In a study reported in 2010, patients with rising PSA levels who had been treated with radiation as the primary treatment for prostate cancer drank a soy beverage daily (providing approximately 65-90 mg isoflavones) for 6 months. The results showed that the soy beverage was well-tolerated and was associated with an increase in PSA doubling time. These findings suggested that drinking the soy beverage may have helped to slow the progression of prostate cancer.[25]
In one small (n = 20), open-label study, patients with rising PSA levels following previous therapy consumed soy milk three times a day (141 mg isoflavonoid/day) for 12 months. The results showed that drinking soy milk was associated with a greater than 50% decline in PSA level in one patient and decreases in the rate of rise in serum PSA in 14 patients.[26]
In another study, prostate cancer patients received genistein-rich supplements (450 mg genistein/day, plus 450 mg other aglycone isoflavones/day) for 6 months. The majority of patients who were undergoing active surveillance exhibited either no rise in PSA level or a decline of less than 50%.[27] In a similar study, prostate cancer patients undergoing active surveillance were randomly assigned to receive a placebo or an isoflavone supplement containing high doses of genistein and daidzein (450 mg genistein, 300 mg daidzein, and other isoflavones) for 6 months. Then, for an additional 6 months, all participants received the isoflavone supplement. Although treatment with the supplements raised serum concentration levels of genistein and daidzein, there was no effect on PSA levels.[28]
In a study reported in 2011, prostate cancer patients scheduled for radical prostatectomy were randomly assigned to receive a placebo or 30 mg genistein daily for 3 to 6 weeks before surgery. Among the patients who received genistein, serum PSA levels decreased by 7.8%, whereas serum PSA levels increased by 4.4% in patients who received the placebo; this difference approached statistical significance (P = .051). In addition, the genistein intervention resulted in significantly lower levels of total cholesterol compared to placebo treatment (P = .013).[29]
In a phase II, randomized, double-blind, placebo-controlled trial [30,31] of men with localized prostate cancer (Gleason score 2–6) who were administered isoflavones (80 mg/day) or a placebo, significant increases in plasma isoflavones (P ≤ .001) were observed from baseline to 4 and 12 weeks in the isoflavone-treated group compared with placebo. Although greater mean reduction of serum-free testosterone was observed in men in the isoflavone-treated group than in men in the placebo group, these changes were not statistically significant for this duration of intervention (P = 0.3). Increasing concentrations of plasma isoflavones daidzein (P = .02) and genistein (P = .01) in the isoflavone-treated group was inversely correlated with changes in serum PSA, compared with the placebo arm.
In another phase II, multidose, randomized placebo-controlled trial,[30] 45 men with localized prostate cancer received supplements with either 40, 60 or 80 mg of purified isoflavones or no supplement from the time of biopsy to prostatectomy. Significant increases in plasma isoflavones were observed with all isoflavone doses, compared with placebo, and significant increases in serum total estradiol were observed in the 40 mg and 60 mg isoflavone-treated arms. However, significant increases in serum-free testosterone were observed in the 60 mg isoflavone-treated arm. Compared with the control group and other treatment arms, the 40 mg isoflavone-treated arm had the lowest percentage of cells expressing Ki-67, although this was not statistically significant for this sample size and duration of intervention. This study concluded that 40 mg of isoflavones may be the best dose to use in a future definitive, larger phase II clinical trial to evaluate purified isoflavones in prostate carcinogenesis.
Soy protein
In one study, early-stage prostate cancer patients were randomly assigned to receive a soy protein supplement (60 mg/day isoflavones) or a placebo daily for 12 weeks. Patients who received the soy protein supplement exhibited larger decreases in total serum PSA and free testosterone than did patients who received the placebo, but these differences were not statistically significant.[32]
Whole soy products
Clinical studies have been conducted in prostate cancer patients to test soy as a possible treatment for prostate cancer. In one study, prostate cancer patients scheduled to undergo radical prostatectomy were randomly assigned to receive soy supplements (three 27.2 mg tablets/day; each tablet contained 10.6 mg genistein, 13.3 mg daidzein, and 3.2 mg glycitein) or a placebo for 2 weeks before surgery. The isoflavone concentration in prostatic tissue was six-fold higher than in serum following treatment with the soy supplements, suggesting that the prostate may accumulate potentially anticarcinogenic levels of isoflavones.[33] In another study, prostate cancer patients scheduled for radical prostatectomy were instructed to eat bread containing high levels of phytoestrogens (soy or soy + linseed; 117 mg/day isoflavones) or low levels of phytoestrogens (wheat bread) until surgery. Patients who ate the high-phytoestrogen bread saw more favorable changes in PSA levels than did patients who ate the wheat bread, indicating that diets rich in phytoestrogens may help to reduce risk of prostate cancer development and progression.[34]
In another small study, ten men with prostate cancer recurrence were advised to consume three 8-ounce glasses of soy milk every day for 2 years. Clinical benefits (i.e., decreased, attenuated, or stabilized PSA) were observed in five of the ten participants, suggesting that soy products may have positive effects in some prostate cancer patients.[35]
Management of hormone therapy side-effects
Androgen deprivation therapy is commonly used for locally advanced and metastatic prostate cancer. However, this treatment is associated with a number of adverse side effects including sexual dysfunction, decreased quality of life, and changes in cognition. In one study, men undergoing androgen deprivation therapy were randomly assigned to receive a placebo or an isoflavone supplement (soy protein powder mixed with beverages; 160 mg/day isoflavones) for 12 weeks. The study results showed no improvement in side effects following isoflavone treatment compared with placebo treatment.[36]
Effects on inflammatory parameters
In another study of men undergoing androgen deprivation therapy, participants were randomly assigned to receive high-dose isoflavone supplements (providing 160 mg/day total isoflavones and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein) or a placebo for 12 weeks. The results showed no difference between the two groups in PSA levels or in levels of metabolic and inflammatory parameters (e.g., glucose, interleukin-6).[37]
Prostaglandins promote inflammation and may contribute to cancer by increasing cell proliferation and inhibiting apoptosis. The findings of a study reported in 2009 suggest that soy isoflavones may have chemopreventive effects via inhibition of the prostaglandin pathway. In the study, prostate cancer patients scheduled to undergo prostatectomy were randomly assigned to receive a placebo or a soy isoflavone supplement (providing 81.6 mg/day isoflavones) for at least 2 weeks before surgery. The results showed a significant decrease in COX-2 mRNA levels (P < .01) and significant increases in p21 mRNA levels (P < .01) in prostatectomy specimens obtained from the soy-supplemented group compared with specimens from the placebo group.[10]
Current Clinical Trials
Check NCI's list of cancer clinical trials for CAM clinical trials on soy isoflavones for prostate cancer and soy protein isolate for prostate cancer that are actively enrolling patients.
General information about clinical trials is also available from the NCI Web site.
Adverse Effects
Overall, soy was well tolerated in clinical studies of prostate cancer patients.[22,24,26,28,33,36] The most commonly reported side effects were gastrointestinal symptoms.[25,27,28] In addition, one study reported that a participant withdrew due to insomnia.[25]
- Zyflamend is a dietary supplement that contains extracts of rosemary, turmeric, ginger, holy basil, green tea, hu zhang, Chinese goldthread, barberry, oregano, and Baikal skullcap.
- The individual components of Zyflamend have anti-inflammatory and possible anticarcinogenic properties.
- In various preclinical studies, Zyflamend has been shown to suppress the expression of certain genes involved in the inflammatory response and in cancer progression, such as cyclooxygenase 1(COX-1), COX-2, 5-lipoxygenase (5-LOX), and 12-LOX.
- In other preclinical studies, Zyflamend has demonstrated single-agent anticancer activity, and the capacity to be combined with hormonal and chemotherapy agents for improved cancer suppression.
- Results of a phase I study of Zyflamend suggest that use of this supplement is not associated with serious toxicity or adverse effects.
General Information and History
Zyflamend is a dietary supplement that contains extracts of rosemary, turmeric, ginger, holy basil, green tea, hu zhang (Polygonum cuspidatum, a source of resveratrol), Chinese goldthread, barberry, oregano, and Baikal skullcap. The individual components of Zyflamend have anti-inflammatory and possible anti-carcinogenic properties. For example, results of a 2011 study suggest that Zyflamend may inhibit the growth of melanoma cells.[1]
The extracts in Zyflamend have been shown to have anti-inflammatory effects via inhibition of cyclooxygenase (COX) activity. COXs are enzymes that convert arachidonic acid into prostaglandins, which are thought to play a role in tumor development and metastasis. One COX enzyme, COX-2, is activated during chronic disease states, such as cancer.[2]
The antitumorigenic mechanisms of action of Zyflamend are unknown, but, according to one study, Zyflamend may suppress activation of nuclear factor-kappa B (NF-kappa B) (a nuclear transcription factor involved in tumorigenesis) and NF-kappa B–regulated gene products.[3]
Preclinical/Animal Studies
In vitro studies
In a study reported in 2012, human prostate cancer cells were treated in vitro with Zyflamend. Cells treated with the supplement at concentrations ranging from 0.06 to 0.5 μL /mL exhibited dose-dependent decreases in androgen receptor and prostate-specific antigen (PSA) expression levels, compared with cells treated with the dimethyl sulfoxide vehicle control. Prostate cancer cells that were treated with a combination of Zyflamend (0.06 μL/mL) and bicalutamide (25 μM), an androgen receptor inhibitor, showed reductions in cell growth, PSA expression, and anti-apoptotic protein expression, compared with cells treated with Zyflamend or bicalutamide alone.[4]
Although the individual components of Zyflamend have been shown to influence COX activity, one study examined the effects of the drug on COX-1 and COX-2 in prostate cancer cells. The results revealed that Zyflamend, at a concentration of 0.9 μL/mL, was effective in inhibiting the activity of both COX-1 and COX-2 in a biochemical assay; at 0.45 μL/mL Zyflamend, a similar extent of COX-2 inhibition was observed, but the level of COX-1 inhibition was reduced by 50%. At a concentration of 0.1 μL/mL, Zyflamend effectively inhibited growth of prostate cancer cells and increased the level of caspase-3, a pro-apoptotic enzyme. However, a separate experiment indicated that the prostate cancer cells used in the study (LNCaP cells, which are androgen sensitive) did not express high levels of COX-2, suggesting that Zyflamend's effects on prostate cancer cells may result from a COX-independent mechanism.[2]
The lipoxygenase isozymes 5-LOX and 12-LOX are also proteins associated with inflammation and tumor growth. In a 2007 study, the effects of Zyflamend on 5-LOX and 12-LOX expression were investigated. The findings indicated that 0.25–2 μL/mL Zyflamend produced decreases in 5-LOX and 12-LOX expression in PC3 prostate cancer cells (cells that have high metastatic potential). The supplement also inhibited cell proliferation and induced apoptosis. In addition, Zyflamend treatment resulted in a decrease in Rb phosphorylation (Rb proteins control cell-cycle -related genes). These results indicate that Zyflamend may inhibit prostate cancer cell growth through a variety of mechanisms.[5]
In a 2011 study, human prostate cancer cells were treated with Zyflamend (200 µg /mL). After 48 hours of treatment, a statistically significant reduction in cell growth was observed for Zyflamend-treated cells, compared with control cells (P < .005). In another experiment, prostate cancer cells were treated with insulin-like growth factor -1 (IGF-1; 0–100 ng /mL) alone or in combination with Zyflamend (200 µg/mL). Cells treated with IGF-1 alone exhibited statistically significant, dose-dependent increases in cell proliferation, whereas cells treated with both IGF-1 and Zyflamend showed significant decreases in cell proliferation. Zyflamend was also shown to decrease cellular levels of the IGF-1 receptor and the androgen receptor in prostate cancer cells.[6]
Animal studies
Additional evidence that Zyflamend promotes apoptosis in cancer cells was obtained in laboratory and animal studies reported in 2012.[7] Treatment of human colorectal carcinoma cell lines in vitro with Zyflamend was shown to significantly down regulate expression of anti-apoptotic proteins, up regulate expression of Bax (a pro-apoptotic protein), and increase expression of death receptor 5 (DR5), a receptor important in apoptosis. Moreover, when nude mice with pancreatic cancer cell implants were randomly assigned to receive Zyflamend or a control treatment for 4 weeks, tumor cells from the Zyflamend-treated mice showed significant reductions in anti-apoptotic proteins and significantly increased expression of DR5, compared to tumor cells from control-treated animals.
In a 2011 study, mice were also implanted with pancreatic cancer cells and then treated with gemcitabine and/or Zyflamend. The combination treatment resulted in a significantly greater decrease in tumor growth than did treatment with gemcitabine or Zyflamend alone. Other findings from this study suggest that Zyflamend exerted its effects by sensitizing the pancreatic tumors to gemcitabine through suppression of multiple targets linked to tumorigenesis.[8]
Human Studies
Intervention studies
In one case report, a patient with high-grade prostatic intraepithelial neoplasia (HGPIN) received Zyflamend 3 times daily for 18 months. Zyflamend did not affect this patient's PSA level, but, after 18 months, repeat core biopsies of the prostate did not show PIN or cancer.[9]
In a 2009 phase I study designed to assess safety and toxicity, patients with HGPIN were assigned to take Zyflamend (780 mg) 3 times daily for 18 months, plus combinations of dietary supplements (i.e., probiotic supplement, multivitamin, green and white tea extract, Baikal skullcap, docosahexaenoic acid, holy basil, and turmeric). Zyflamend and the additional dietary supplements were well tolerated by the patients, and no serious adverse events occurred. After 18 months of treatment, 60% of the study subjects had only benign tissue at biopsy, 26.7% had HGPIN in one core, and 13.3% had prostate cancer.[10]
Adverse Effects
Zyflamend was well tolerated in the previously described 2009 clinical study. Mild heartburn was reported in 9 of 23 subjects, but it resolved when the study supplements were taken with food. No serious toxicity or adverse events were reported in the study.[10]
Changes to This Summary (08 / 06 / 2013)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Cancer Complementary and Alternative Medicine Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Complementary and Alternative Medicine Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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The lead reviewers for Prostate Cancer, Nutrition, and Dietary Supplements are:
- Donald I. Abrams, MD (UCSF Osher Center for Integrative Medicine)
- Nagi B. Kumar, PhD, RD, FADA (Fellow of the American Dietetic Association)
- Jeffrey D. White, MD (National Cancer Institute)
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National Cancer Institute: PDQ® Prostate Cancer, Nutrition, and Dietary Supplements. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/cam/prostatesupplements/healthprofessional. Accessed <MM/DD/YYYY>.
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