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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.
This cancer information summary provides an overview of the use of various foods and dietary supplements for reducing the risk of developing prostate cancer or for treating prostate cancer. This summary includes the history of research, reviews of laboratory and animal studies, and results of clinical trials on the following foods or dietary supplements:
Each type of dietary supplement or food will have a dedicated section in the summary, and new topics will be added over time. Note: A separate PDQ summary on PC-SPES is also available.
Prostate cancer is the most common noncutaneous cancer affecting men in the United States. From 2008 to 2012, the median age of diagnosis of prostate cancer was 66, and the incidence rate was 138 cases per 100,000 men per year.
Many studies suggest that complementary and alternative medicine (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 study that 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.
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). 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. 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. 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.
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). 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.
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%.
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. In two separate studies, 58% of respondents told their doctors about their CAM usage.[4,6]
How do prostate cancer patients decide whether or not to use CAM? A qualitative study published in 2005 described results from interviews with prostate cancer patients. The study identified differences in thinking patterns between CAM users and nonusers and suggested that no specific theme led patients to CAM; instead, patients were directed by a combination of ideas. For example, the perception of CAM as harmless was associated with the belief that conventional medicine resulted in many negative side effects. Results of a 2003 qualitative study suggested that decision making about CAM treatments by prostate cancer patients depended on both fixed (e.g., medical history) and flexible (e.g., a need to feel in control) decision factors.
Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.
Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be considered an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.
Refer to the PDQ summary on Prostate Cancer Prevention for more information on prostate cancer prevention.
This section contains the following key information:
General Information and History
Calcium, the most abundant mineral in the body, is found in some foods, added to others, available as a dietary supplement, and present in some medicines (such as antacids). Calcium is required for vascular contraction and vasodilation, muscle function, nerve transmission, intracellular signaling, and hormonal secretion, although less than 1% of total body calcium is needed to support these critical metabolic functions.Serum calcium is very tightly regulated and does not fluctuate with changes in dietary intake; the body uses bone tissue as a reservoir for, and source of, calcium to maintain constant concentrations of calcium in blood, muscle, and intercellular fluids.
The major sources of calcium in the U.S. population are food and dietary supplements. According to recent National Health and Nutrition Examination Survey data, U.S. adults obtain 38% of their dietary calcium from milk and milk products, such as yogurt and cheese. Nondairy sources include vegetables, such as Chinese cabbage, kale, and broccoli. Spinach provides calcium, but its bioavailability is poor. Most grains do not have high amounts of calcium unless they are fortified; however, they contribute calcium to the diet because they contain small amounts of calcium, and people consume them frequently. Foods fortified with calcium include many fruit juices and drinks, tofu, and cereals. In the United States, dietary supplements, including calcium supplements, are commonly used to prevent chronic diseases, including cancer.Mean dietary calcium intakes for males aged 1 year and older ranged from 871 to 1,266 mg/day depending on life stage group (i.e., infant, adolescent, or adult). About 43% of the U.S. population uses dietary supplements containing calcium, which increases calcium intake by about 330 mg/day among supplement users.[1,2]
To evaluate the association between calcium intake and prostate cancer mortality and morbidity, it may be important to assess objective, biological markers of calcium, include data that account for nutritional and supplemental calcium intake, and control for other confounding factors. However, studies of association between calcium and prostate cancer have been limited to nutritional sources of calcium, such as dairy products. Although more than half of the U.S. population uses vitamin and mineral supplements (at an annual cost of over 11 billion dollars), few studies include supplement use in the association of disease risk, including prostate cancer or mortality rates.[1,2] (Refer to the PDQ summary on Prostate Cancer Prevention for more information.)
In vitro studies
Prostate cancer cells were treated with bovine milk, almond milk, soy milk, casein, or lactose in a 2011 study. Treatment with bovine milk resulted in growth stimulation of LNCaP prostate cancer cells. Growth of prostate cancer cells was not affected by treatment with soy milk, and treatment with almond milk resulted in growth inhibition.
In vivo studies
One study investigated the effects of dietary calcium on prostate tumor progression in LPB-Tag transgenic mice. The animals consumed low (0.2%) or high (2.0%) calcium diets and were sacrificed at age 5, 7, or 9 weeks. Tumor weight and progression were similar in mice that were fed low- and high-calcium diets.
A 2012 study examined the impact of dietary vitamin D and calcium on prostate cancer growth in athymic mice. The mice were injected with human prostate cancer cells and were randomly assigned to receive specific diets (e.g., high calcium/vitamin D or normal calcium/no vitamin D). The mice that received the normal calcium/vitamin D-deficient diet exhibited significantly greater (P < .05) tumor volumes than did mice that received the other diets.
Several epidemiological studies have found an association between high intakes of calcium, dairy foods, or both, and an increased risk of developing prostate cancer.[7,8,9] However, others have found only a weak relationship, no relationship, or a negative association between calcium intake and prostate cancer risk.[10,11,12,13] On the basis of these studies, interpretation of the evidence is complicated by the difficulty of separating the effects of dairy products from the effects of calcium. Additionally, earlier epidemiological studies had several limitations. The association of calcium intake with prostate cancer was limited to evidence from self-reported food frequency questionnaires of nutritional sources of calcium, with a focus on dairy foods.[14,15] Competing risk factors, such as other major nutrients in dairy (i.e., fats) and concomitant and confounding factors (i.e., age, body mass index, steroid hormones, and other metabolic events in the causal pathway) were not accounted for. Additionally, no objective markers of calcium, such as serum calcium, were obtained from these cohorts. Observational studies overall, however, suggest that high total calcium intake may be associated with increased risk of advanced and metastatic prostate cancer, compared with lower intake of calcium.[11,12,16,17,18] Another analysis of 886 prostatectomy patients found an increased risk of being diagnosed with more aggressive disease in men with higher calcium intakes. The hazard of disease recurrence after surgical treatment was increased in men with both very low and high calcium intakes. Additional research is needed to clarify the effects of calcium and/or dairy products on prostate cancer risk and elucidate potential biological mechanisms.
In a randomized clinical trial published in 2005, 672 men received either 3 g of calcium carbonate (1,200 mg calcium) or placebo daily for 4 years and were followed for 12 years. During the first 6 years of the study, there were significantly fewer prostate cancer cases in the calcium group compared with the placebo group. However, this difference was no longer statistically significant at the 10-year evaluation.
A meta-analysis published in 2005 reported that there may be an association between increased risk of prostate cancer and greater consumption of dairy products and calcium.
A 2008 meta-analysis reviewed 45 observational studies and found no evidence of a link between dairy products and risk of prostate cancer. A meta-analysis of cohort studies published between 1996 and 2006 found a positive association between milk and dairy product consumption and risk of prostate cancer.
In a recent review, the U.S. Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews, conducted meta-analyses using Mantel-Haenszel fixed effects models for overall cancer incidence, cardiovascular disease incidence, and all-cause mortality. Vitamin D and/or calcium supplementation showed no overall effect on cancer incidence and mortality, including prostate cancer. In a meta-analysis of the association of calcium without the coadministration of vitamin D, a reduced risk of prostate cancer was observed, although there were only a few events.
In 2007, the World Cancer Research Fund/American Institute for Cancer Research reported that there was probable evidence that diets high in calcium increase the risk of prostate cancer and that there is limited suggestive evidence that milk and dairy products also increase the risk. Since publication, 18 additional studies that evaluated dairy or calcium intake and the risk of prostate cancer have been published. A 2015 meta-analysis of this literature concluded that high intakes of dairy products, milk, low-fat milk, cheese, total dietary calcium, and dairy calcium may increase prostate cancer risk. Supplemental calcium and nondairy calcium were not associated with an increased risk, although supplemental calcium was associated with an increased risk of fatal prostate cancer. The authors suggested that this association needs additional study.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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. 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 whereby 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. Oolong, a third major type of tea, contains polyphenols that are partially oxidized.
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, and there is evidence that green tea may protect against various forms of cancer. Many of the health benefits associated with tea have been attributed to polyphenols. GTCs include EGCG, EC, EGC, ECG, and oligomeric proanthocyanidins derived from these catechin monomers. Among these compounds, EGCG is the most abundant catechin in green tea and has been widely researched; however, it is also classified as a promiscuous compound. Laboratory, preclinical, and early-phase clinical trials have identified EGCG as one of the most potent modulators of molecular pathways thought to be relevant to prostate carcinogenesis. Tea leaves also contain considerable amounts of oligomeric catechins, in particular, 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.
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.
In a 2011 study, human prostate cancer cells were treated initially with EGCG (concentrations, 1.5-7.5 μM) and then with radiation. The results showed that exposing cells to EGCG for 30 minutes before radiation significantly reduced apoptosis, compared with radiation alone.
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.
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.
Advances in nanotechnology-nanochemoprevention -may result in more-effective administration of EGCG to men at risk of developing prostate cancer. Prostate cancer cells were treated with EGCG-loaded (100 μM EGCG) nanoparticles or free EGCG. Although both treatments decreased cell proliferation and induced apoptosis, the nanoparticle treatment had a greater effect at a lower concentration than did free EGCG. This finding suggests that using a nanoparticle delivery system for EGCG may increase its bioavailability and improve its chemopreventive actions. In one study, EGCG (30 μM) was encapsulated in nanoparticles that contained polymers targeting prostate-specific membrane antigen (PSMA). Prostate cancer cells treated with this intervention exhibited decreases in proliferation; however, the intervention did not affect nonmalignant control cells. The results suggest that this delivery system may be effective for selective targeting of prostate cancer cells.
Research also suggests that glutathione-S-transferase pi (GSTP1) may be a tumor suppressor and that hypermethylation of certain regions of this gene (i.e., CpG islands) may be a molecular marker of prostate cancer. Increased methylation leads to silencing of the gene. A set of experiments investigated the effects of green tea polyphenols on GSTP1 expression. Treatment of different types of prostate cancer cells with green tea polyphenols (1-10 μg /mL Polyphenon E) resulted in re-expression of GSTP1 by reversing hypermethylation and by reducing expression of methyl-CpG-binding domain proteins, which bind to methylated DNA. These results indicate that green tea polyphenols may have chemopreventive effects via actions on gene-silencing processes.
The results of a 2011 study suggested that green tea polyphenols may exert anticancer effects by inhibiting histone deacetylases (HDACs). Class I HDACs are often overexpressed in various cancers, including prostate cancer. Treatment of human prostate cancer cells with green tea polyphenols (10-80 μg/mL Polyphenon E) resulted in decreased class I HDAC activity and increased expression of Bax, a proapoptotic protein.
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]
Animal models have been used in several studies investigating the effects of green tea on prostate cancer. In one study, TRAMP mice were given access to water or GTC-treated water (0.3% GTC solution; this exposure mimics human consumption of 6 cups of green tea daily). After 24 weeks, water-fed TRAMP mice had developed prostate cancer, whereas mice treated with GTCs showed only prostatic intraepithelial neoplasia lesions, suggesting that GTCs may help delay the development of prostate tumors. In another study, castrated mice were injected with prostate cancer cells and then treated daily with intraperitoneal injections of 1 mg EGCG or vehicle. Treatment with EGCG resulted in reductions in tumor volume and decreases in serum PSA levels compared with vehicle treatment.
In a 2011 study, EGCG was shown to be an androgen antagonist; when added to prostate cancer cells, EGCG physically interacted with the androgen receptor's ligand-binding domain. In addition, mice implanted with tumor cells and treated with EGCG (intraperitoneal injections of 1 mg EGCG, 3/wk) exhibited less androgen receptor protein expression than did mice that were treated with vehicle.
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). 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. In one study, EGCG treatment (0.06% EGCG in drinking water; this exposure mimics human consumption of 6 cups of green tea/d) was initiated in TRAMP mice at age 12 or 28 weeks. EGCG treatment suppressed HGPIN in mice treated at age 12 weeks; however, EGCG did not prevent prostate cancer development in mice that began treatment at age 28 weeks.
Using the TRAMP mouse model, one study demonstrated that oral infusion of GTP extract at a human-achievable dose (equivalent to 6 cups of green tea/d) significantly delayed primary tumor incidence and tumor burden, as assessed sequentially by magnetic resonance imaging; decreased prostate weight (64% of baseline) and genitourinary weight (72%); inhibited serum insulin-like growth factor -1; restored insulin-like growth factor-binding protein-3 (IGFBP-3) levels; and produced marked reduction in the protein expression of proliferating cell nuclear antigen in the GTP-fed TRAMP mice, compared with water-fed TRAMP mice. Furthermore, GTP consumption caused significant apoptosis, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of development, progression, and metastasis to distant organ sites. In another study, 119 male TRAMP mice and 119 C57BL/6J mice were treated orally with one of three doses of Polyphenon E (200, 500, or 1,000 mg/kg/d) in drinking water ad libitum, replicating human-achievable doses. Safety and efficacy assessments were performed at baseline and when mice were 12, 22, and 32 weeks old. Results indicated that the number and size of tumors in treated TRAMP mice were significantly decreased, compared with untreated animals. In untreated 32-week-old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period.
Animal safety studies
In a National Cancer Institute (NCI) Division of Cancer Prevention (DCP)-sponsored, 9-month, oral toxicity study, Polyphenon E was administered (200, 500, or 1,000 mg/kg/d) to fasted male and female beagle dogs. The study was terminated prematurely because of excessive loss of animals due to morbidity and mortality in all treatment groups. These studies have revealed some unique dose-limiting lethal liver, gastrointestinal, and renal toxicities. Gross necropsy revealed therapy-induced lesions in the gastrointestinal tracts, livers, kidneys, reproductive organs, and hematopoietic tissues of treated male and female dogs. In the 13-week follow-up study, the no-observed-adverse-effect-level was greater than 600 mg/kg per day of Polyphenon E. When the study was conducted in nonfasted dogs under the same testing conditions and dose levels, the results were unremarkable. Nonspecific toxicity and a tenfold reduction in the maximum tolerated dose in fasted beagle dogs compared with fed beagle dogs were seen using a purified GTC containing less than 77% EGCG. However, in the follow-up NCI DCP-sponsored study in fed dogs compared with fasted dogs using several Polyphenon E formulations, no deaths occurred, suggesting that fasting may have rendered the target organ systems more vulnerable to the effects of green tea extract.
In a study  of several doses of a standardized Polyphenon E targeting TRAMP mice, no liver or other toxicities were observed. Long-term (32 weeks) treatment with Polyphenon E (200, 500, and 1,000 mg/kg/d) was safe and well tolerated, with no evidence of toxicity in C57BL/6J mice. The C57BL/6J mice showed no differences in appearance or behavior, or changes in prostate and body weights after 32 weeks of treatment for all three doses of Polyphenon E. No discernible histopathological changes were observed in the liver, lung, or any prostate lobe of C57BL/6J mice treated with the three different doses of Polyphenon E.  Similarly, another preclinical study  did not observe liver or other toxicities with standardized EGCG at doses of up to 500 mg EGCG preparation/kg per day.
The relationship between green tea intake and prostate cancer has been examined in several epidemiological 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.[27,28,29,30,31] In Asian countries with a high per capita consumption of green tea, prostate cancer mortality rates are among the lowest in the world, and the risk of prostate cancer appears to be increased among Asian men who abandon their original dietary habits upon migrating to the United States. Overall, findings from population studies suggest that green tea may help protect against prostate cancer in Asian populations.[26,33] 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 GTCs.
Phase I/II intervention studies to date have reported bioavailability of EGCG in plasma using single and repeated doses of EGCG, noting higher plasma EGCG concentrations in fasting conditions relative to fed conditions.[34,35,36] Studies using varying doses (400 mg, 800 mg EGCG) of GTCs and Polyphenon E administered in single and repeated dosing schedules for 3 to 6 weeks have reported median maximum concentrations of EGCG ranging from 68.8 ng /mL to 390.36 ng/mL (refer to Table 1).[36,37,38] Not all individuals in the treatment arms of these and other studies [29,39,40] had detectable levels of EGCG, indicating potential variation in individual absorption. Catechins other than EGCG were nondetectable or below quantifiable levels in the plasma in many trials.
Tissue levels of catechins have also been quite variable when examined. Notably, catechin levels in prostate tissue were low to undetectable after the administration of Polyphenon E in one preprostatectomy study. 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 enzyme that methylates EGCG) gene.
In a single-center Italian study, 60 men diagnosed with HGPIN were randomly assigned to receive GTC capsules (GTCs, 600 mg/d) 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 GTC group were diagnosed with prostate cancer. After 1 year, nine men in the placebo group and one man in the GTC group were diagnosed with prostate cancer (P < .01). These findings suggest that GTCs may help prevent prostate cancer in groups at high risk of the disease. In 2008, follow-up results to this study were published, indicating that the inhibitory effects of GTCs on prostate cancer progression were long-lasting. However, nearly all of the prostate cancer risk reduction in that study occurred at the 6-month biopsy, suggesting that the results may have been biased by a nonrandom distribution of occult prostate cancer at baseline. No reduction in serum PSA was observed in the treatment arm of this study compared with placebo.
A larger, multicenter, randomized trial (NCT00596011) in the United States studied 97 men with either HGPIN or atypical small acinar proliferation who received a GTC mixture (Polyphenon E, 200 mg, bid). Atypical small acinar proliferation is an entity that reflects a broad group of lesions of varying clinical significance with insufficient cytological or architectural atypia to establish a definitive diagnosis of prostate cancer.[8,26] Results indicated that a daily intake of a standardized, decaffeinated catechin mixture containing 400 mg EGCG per day for 1 year, accumulated in the plasma, was well tolerated,Level of evidence 1A but did not significantly reduce the incidence of prostate cancer in the treatment group with Polyphenon E (5/49, 10.2%) compared with the placebo group (9/48, 18.8%; P = .25). However, in a prespecified secondary analysis performed in men with HGPIN (without atypical small acinar proliferation) at baseline, Polyphenon E was associated with a significant decrease in the composite endpoint (prostate cancer plus atypical small acinar proliferation) (3/26 Polyphenon E vs. 10/25 placebo, P < .024), with these findings largely driven by the absence of atypical small acinar proliferation on end-of-study biopsy on the Polyphenon E arm (Polyphenon E [0/26] vs. placebo arm [5/25]). Because there is no clear evidence that HGPIN and atypical small acinar proliferation represent steps on a linear path to prostate cancer, these findings should be interpreted with caution. A comparison of the estimated overall treatment effect showed a significantly greater reduction of serum PSA in men treated with Polyphenon E compared with controls (-0.87 ng/mL; 95% confidence interval, -1.66 to -0.09). Although the findings of this U.S. study appear to refute the large effect size suggested by the Italian study [40,42,43] that reported a 90% reduction in prostate cancer among men with HGPIN, overall, the randomized controlled trials have shown a decreased rate of progression to atypical small acinar proliferation or prostate cancer in men with HGPIN treated with GTCs.
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. In an open label, phase II trial, 113 men with prostate cancer were randomly assigned to drink six cups of green tea, black tea, or water before radical prostatectomy. Ninety-three patients completed the intervention. Although there were no significant differences in markers of proliferation, apoptosis, and oxidation in the prostatectomy tissue, only the men drinking green tea demonstrated small but significant decreases in PSA levels (P = .04).
In an open label, phase II clinical study, prostate cancer patients scheduled for radical prostatectomy consumed four Polyphenon E tablets containing tea polyphenols, 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).
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.
Advanced prostate cancer
In a small, single-arm study, hormone-refractory prostate cancer patients received capsules of green tea extract twice daily (total polyphenols, 375 mg/d); not specified by polyphenol type) 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.
In a 2003 study, patients with androgen-independent metastatic prostate cancer consumed 6 g of powdered green tea extract daily for up to 4 months. Among 42 participants, 1 patient exhibited a 50% decrease in serum PSA level compared with 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.
The safety of tea and tea compounds is supported by centuries of consumption by the human population. The bioavailability and tolerance to GTC at doses ranging from 600 to 1,000 mg EGCG at single and multiple doses, and a duration of a few days to 1 year has been well documented in phase I/II clinical trials.[34,35,36,37,38,41,44,45,46,47,48] The authors of a phase I trial of oral green tea extract in adult patients with solid tumors reported that a safe dose of green tea extract (1.0 g/m2, tid) was equivalent to seven to eight Japanese cups (120 mL) of green tea three times per day for 6 months. The authors concluded that the side effects (neurological and gastrointestinal) of the green tea extract preparation were caffeine related, and not from EGCG. In four phase I, single-dose, and multidose studies that targeted healthy volunteers who took a botanical drug substance containing a mixture of catechins, Polyphenon E, and a dose range of 200 to 1,200 mg EGCG was well tolerated.[31,32,38,39,40,42,43]Adverse effects with a possible relationship to the study drug reported in these studies have been grade 2 to 3 and included asthenia, headache, abdominal pain, chest pain, diarrhea, dyspepsia, eructation, flatulence, nausea, vomiting, dizziness, vasodilation, and rash. These studies have demonstrated that although increased oral bioavailability occurs when GTCs are consumed in a fasting state, increased gastrointestinal toxicity is also more common. Gastrointestinal adverse effects were usually mild and seen most often at the higher dose levels. Onset of gastrointestinal events typically occurred within 2 to 3 hours of dosing and resolved within 2 hours. No grade 3 or higher events were reported with a possible relationship to the study drug.
Green tea has been well tolerated in clinical studies of men with prostate cancer.[41,46] In a 2005 study, the most commonly reported side effects were gastrointestinal symptoms. These symptoms were mild for all but two men, who experienced severe anorexia and moderate dyspnea. With the duration of intervention in these studies ranging from single, one-time administration to a maximum of 90 days, the safety data from these studies are limited to short-term safety of EGCG and GTCs.
Data from clinical trials [40,42] report long-term safety of EGCG containing GTCs, for use in men with precursor lesions of prostate cancer for prevention of prostate cancer. One study  administered approximately 300 mg EGCG per day for 1 year without any reported toxicities.
In the recently completed U.S. trial, 400 mg of EGCG containing Polyphenon E was administered for 1 year to nonfasting men with HGPIN and atypical small acinar proliferation. More possible and probable grade 2 through grade 3 events in men who received Polyphenon E were observed and compared with those in men who received placebo. Only one man who received Polyphenon E reported grade 3 nausea, which was determined to possibly be related to the study agent.
In recent years, oral consumption of varying doses and compositions of green tea extracts (GTEs) has been associated with several instances of hepatotoxicity.[24,36,50,51,52] 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 GTEs, 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 GTE capsules. The capsules contained Polyphenon 70A (a concentrated, enriched, and pasteurized hot-water extract of green tea) and 120 mg GTE. 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. 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. The U.S. Food and Drug Administration's Division of Drug Oncology Products has recommended that Polyphenon E be taken with food by subjects participating in clinical studies. In addition, liver function tests should be considered while individuals are on treatment.
Lycopene is a phytochemical that belongs to a group of pigments known as carotenoids. It is red and lipophilic. As a natural pigment made by plants, lycopene helps to protect plants from light-induced stress, and it also transfers light energy during photosynthesis. Lycopene is found in a number of fruits and vegetables, including apricots, guavas, and watermelon, but the majority of lycopene consumed in the United States is from tomato-based products.
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. Lycopene may protect against cardiovascular disease by decreasing cholesterol synthesis and increasing the degradation of low-density lipoproteins, although some interventional studies have shown mixed results.
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. However, epidemiological studies 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 not response of clinically evident disease or overall survival and thus have limited translation to practice.[2,6]
On the basis of overall evidence, the association between tomato consumption and reduced risk of prostate cancer is limited.
In vitro studies that have examined a link between lycopene and prostate carcinogenesis have suggested several mechanisms by which lycopene might reduce prostate cancer risk. Lycopene is broken down into a number of metabolites that are thought to have various biological effects, including antioxidant capabilities and a role in gap-junction communication.
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.
In addition, treating prostate cancer cells with lycopene resulted in a significant decrease in the number of lycopene-treated cells in the S phase of the cell cycle, suggesting that lycopene may lower cell proliferation by altering cell-cycle progression. Moreover, apo-12'-lycopenal, a lycopene metabolite, reduced prostate cancer cell proliferation and may modulate cell-cycle progression.
Some studies have suggested that cancer cells have altered cholesterol-biosynthesis pathways. Treating prostate cancer cells with lycopene resulted in dose-dependent decreases in 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (the rate-limiting enzyme in cholesterol synthesis), total cholesterol, and cell growth, and an increase in apoptosis. However, adding mevalonate prevented the growth-inhibitory effects of lycopene, indicating that the mevalonate pathway may be important to the anticancer activity of lycopene. Lycopene may also affect cholesterol levels in prostate cancer cells by activating the peroxisome proliferator-activated receptor gamma (PPARγ)-liver X receptor alpha (LXRα)-ATP-binding cassette, subfamily 1 (ABCA1) pathway, which leads to decreased cholesterol levels and may ultimately result in decreased cell proliferation. ABCA1 mediates cholesterol efflux, and PPARγ has been shown to inhibit the growth and differentiation of prostate cancer cells. In one study, treating prostate cancer cells with lycopene resulted in increased expression of PPARγ, LXRα, and ABCA1 as well as lower total cholesterol. In addition, when the cells were treated with a PPARγ antagonist, cell proliferation increased, whereas treating cells with a combination of the PPARγ antagonist and lycopene decreased cell proliferation.
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. In a study that examined the physiologically relevant concentration of lycopene (2 mmol/L) or placebo for 48 hours on protein expression in human primary prostatic epithelial cells, proteins that were significantly upregulated or downregulated following lycopene exposure were those proteins involved in antioxidant responses, cytoprotection, apoptosis, growth inhibition, androgen receptor signaling, and the AKT /mTOR cascade. These data are consistent with previous studies, suggesting that lycopene can prevent malignant transformation in human prostatic epithelial cells at the stages of cancer initiation, promotion, and/or progression.
A study examining the effect of lycopene on multiple points along the nuclear factor-kappa B (NF-kappa B) signaling pathways in prostate cell lines demonstrated a 30% to 40% reduction in inhibitor of kappa B (I-kappa B) phosphorylation, NF-kappa B transcriptional activity and a significant reduction in cell growth at the physiologically relevant concentration of 1.25 μM or higher. These results provided evidence that the anticancer properties of lycopene may occur through inhibition of the NF-kappa B signaling pathway, beginning at the early stage of cytoplasmic IKK kinase activity, which then leads to reduced NF-kappa B-responsive gene regulation. Additionally, these effects in the cancer cells were observed at concentrations of lycopene that are relevant and achievable in vivo.
Some studies have assessed possible beneficial interactions between lycopene and conventional cancer therapies. In one such study, various types of prostate cancer cells were treated with a combination of lycopene and docetaxel, a drug used to treat patients with castration -resistant prostate cancer, or each drug alone. The combination treatment inhibited proliferation in four of five cell lines to a greater extent than did treatment with docetaxel alone. The findings suggest that the mechanism for these effects may involve the IGF-1 receptor (IGF-1R) pathway.
In a chemoprevention study, 59 transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed diets supplemented with tomato paste or lycopene beadlets (both preparations contained 28 mg lycopene/kg chow). Mice that received lycopene beadlets exhibited a larger reduction in prostate cancer incidence compared with control mice than mice supplemented with tomato paste, suggesting that lycopene beadlets may provide greater chemopreventive effects than tomato paste.
Ketosamines are carbohydrate derivatives formed when food is dehydrated. In one study, FruHis (a ketosamine in dehydrated tomatoes) combined with lycopene resulted in greater growth inhibition of implanted rat prostate cancer cells than did lycopene or FruHis alone. In addition, in a N-methyl-N-nitrosourea/testosterone-induced prostate carcinogenesis model, rats fed a tomato paste and FruHis diet had longer survival times than rats fed only with tomato paste or tomato powder.
Lycopene has also been studied for potential therapeutic effects in xenograft models. In one study, athymic nude mice were injected with human androgen-independent prostate cancer cells and were treated with either lycopene (4 mg/kg body weight or 16 mg/kg body weight) or beta-carotene (16 mg/kg body weight). Supplementing mice with lycopene or beta-carotene resulted in decreased tumor growth. In an in vitro study, the investigators demonstrated the effect of lycopene in androgen-independent prostate cancer cell lines. In another study, nude mice were injected with human prostate cancer cells and treated with intraperitoneal injections of docetaxel, lycopene (15 mg/kg/d) administered via gavage, or a combination of both. Mice exhibited longer survival times and smaller tumors when treated with a combination of docetaxel and lycopene than when they were treated with docetaxel alone.
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 risk of prostate cancer.[7,9,10,11,12,13] Prospective and case-control studies have shown lycopene to be significantly lower in the serum and tissue of patients with cancer than in controls,[7,16,17,18,19,21] while other studies have failed to demonstrate such a connection.
An association between lycopene serum concentration and risk of cancer was also examined in men participating in the Kuopio Ischaemic Heart Disease Risk Factor study in Finland. In this prospective cohort study, an inverse association between lycopene levels and overall cancer risk was observed, suggesting that higher concentrations of lycopene may help lower cancer risk overall. Men with the highest levels of serum lycopene had a 45% lower risk of cancer than did men with the lowest levels of lycopene (risk ratio, 0.55; 95% confidence interval (CI), 0.34-0.89; P = .015). However, when the analysis was restricted to specific cancer types, an association was observed for other cancers (risk ratio, 0.43; 95% CI, 0.23-0.79; P = .007) but not prostate cancer.
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). A 2013 meta-analysis, including four of five cohort studies from the 2004 meta-analysis, two new meta-analyses, and three case-control studies from the previous study plus eight new ones, reported less-convincing evidence for risk reduction. Among men who consumed high amounts of raw tomato products, the RR of prostate cancer was 0.81 (95% CI, 0.59-1.10), compared with men who ate the least amount of raw tomatoes. For men who consumed the most cooked tomato products, the RR was 0.85 (95% CI, 0.69-1.06). The authors concluded that tomatoes may play a modest role in the prevention of prostate cancer.
The National Cancer Institute's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial is an ongoing, prospective study that has been a source of subjects for investigations of an association between lycopene intake and prostate cancer risk. A 2006 study examined lycopene and tomato product intakes and prostate cancer risk among PLCO participants who had been followed 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. 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.
The Health Professionals Follow-up Study obtained dietary information and ascertained total and lethal prostate cancer cases from 1986 through January 31, 2010. Higher lycopene intake was inversely associated with total prostate cancer risk (hazard ratio [HR], 0.91; 95% CI, 0.84-1.00) and lethal prostate cancer risk (HR, 0.72; 95% CI, 0.56-0.94). A subset analysis was restricted to men who had at least one negative PSA test at the onset, to reduce the influence of PSA screening on the association. The inverse association became markedly stronger (HR, 0.47; 95% CI, 0.29-0.75 for lethal prostate cancer). Levels of tumor markers for angiogenesis, apoptosis, and cellular proliferation and differentiation were monitored. Three of the tumor angiogenesis markers were strongly associated with lycopene intake, so that men with higher intake had tumors that demonstrated less angiogenic potential.
At least two studies examined the effect of lycopene blood levels on the risk of high-grade prostate cancer. The first study examined the associations between carotenoid levels and the risk of high-grade prostate cancer, and also considered antioxidant-related genes and tumor instability. This study demonstrated that plasma carotenoids at diagnosis, particularly among men carrying specific somatic variations, were inversely associated with risk of high-grade prostate cancer. Higher lycopene concentrations were associated with less genomic instability among men with low-grade disease, indicating that lycopene may inhibit progression of prostate cancer early in its natural history.
In another study examining whether carotenoid intake and adipose tissue carotenoid levels were inversely associated with prostate cancer aggressiveness, results suggested that diets high in lycopene may protect against aggressive prostate cancer in white Americans and diets high in beta-cryptoxanthin may protect against aggressive prostate cancer in African Americans.
One study investigated the correlation between lycopene blood levels and the rate of progression of prostate cancer. This study examined plasma carotenoids and tocopherols in relation to PSA levels among men with biochemical recurrence of prostate cancer. This study indicated that the plasma cis -lutein/zeaxanthin level at 3 months was inversely related to PSA level at 3 months (P = .0008), while alpha-tocopherol (P = .01), beta-cryptoxanthin (P = .01), and all-trans-lycopene (P = .004) levels at 3 months were inversely related to PSA levels at 6 months. Percentage increase in alpha-tocopherol and trans-beta-carotene levels from baseline to month 3 was associated with lower PSA levels at 3 and 6 months. Percentage increase in beta-cryptoxanthin, cis-lutein/zeaxanthin and all-trans-lycopene was associated with lower PSA levels at 6 months only.
A study examined the association of prediagnosis and postdiagnosis dietary lycopene and tomato product intake with prostate-cancer specific mortality in a prospective cohort of men diagnosed with nonmetastatic prostate cancer. No association between serum lycopene, tomato products, and prostate-cancer specific mortality was observed. Among men with high-risk cancers (T3-T4, Gleason score 8-10, or nodal involvement), consistently reporting lycopene intake that was at or above the median was associated with lower prostate-cancer specific mortality.
The variability in these epidemiological study results may be related to lycopene source; exposure misclassification; inconsistent measures of intake; differences in absorption; differences in individual lycopene metabolism; lack of a dose response; and confounding lifestyle factors, such as obesity, use of tobacco and alcohol, other dietary differences, varying standardization of quantities and compositions of lycopene, geographical location, and genetic risk factors. Most studies have examined the association of lycopene intake with the risk of all prostate cancers and have not separately considered indolent versus aggressive disease. Given these caveats, results based on epidemiological evidence should be interpreted with caution.
A number of clinical studies have been conducted investigating lycopene as a chemopreventive agent and as a potential treatment for prostate cancer.
The bioavailability of lycopene has been examined and demonstrated in several studies relating lycopene to prostate cancer and other diseases. The bioavailability of lycopene is greater in processed tomato products, such as tomato paste and tomato puree, than in raw tomatoes. Lycopene bioavailability has been observed to be highly variable, which may lead to varying biological effects after lycopene consumption. It is postulated that these variations, at least in part, can be attributed to several single nucleotide polymorphisms in genes involved in red-pigment lycopene and lipid metabolism. In a study to define the impact of typical servings of commercially available tomato products on resultant plasma and prostate lycopene concentrations, men scheduled to undergo prostatectomy (n = 33) were randomly assigned to either a lycopene-restricted control group (<5 mg/d) or a tomato soup (2-2¾ cups/d prepared), tomato sauce (142-198 g/d or 5-7 oz/d), or vegetable juice (325-488 mL/d or 11-16.5 fluid oz/d) intervention providing 25 to 35 mg of lycopene per day. The end-of-study prostate lycopene concentration was 0.16 nmol/g (standard error of the mean, 0.02) in the controls, but was 3.5-, 3.6- and 2.2-fold higher in tomato soup (P = .001), sauce (P = .001), and juice (P = .165) consumers, respectively. Prostate lycopene concentration was moderately correlated with postintervention plasma lycopene concentrations (correlation coefficient, 0.60; P = .001), indicating that additional factors have an impact on tissue concentrations. While the primary geometric lycopene isomer in tomato products was all-trans (80%-90%), plasma and prostate isomers were 47% and 80% cis -lycopene, respectively, demonstrating a shift towards cis accumulation. Consumption of typical servings of processed tomato products results in differing plasma and prostate lycopene concentrations. Factors including meal composition and genetics deserve further evaluation to determine their impacts on lycopene absorption, isomerization, and biodistribution.
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. Results of a randomized study published in 2005 demonstrated that cooking diced tomatoes with olive oil significantly increased lycopene absorption compared with cooking tomatoes without olive oil. In another study, 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 study found that combining olive oil, but not sunflower oil, with tomatoes resulted in greater plasma antioxidant activity.
Healthy males participated in a crossover design study that attempted to differentiate the effects of a tomato matrix from those of lycopene by using lycopene-rich red tomatoes, lycopene-free yellow tomatoes, and purified lycopene. Thirty healthy men aged 50 to 70 years were randomly assigned to two groups with each group consuming 200 g/d of yellow tomato paste (lycopene, 0 mg) and 200 g/d of red tomato paste (lycopene, 16 mg) as part of their regular diet for 1 week, separated by a 2-week washout period. Then, in a parallel design, the first group underwent supplementation with purified lycopene (16 mg/d) for 1 week, whereas the second group received a placebo. Sera samples collected before and after the interventions were incubated with lymph node cancer prostate cells to measure the expression of 45 target genes. In this placebo-controlled trial, circulating lycopene concentration increased only after consumption of red tomato paste and purified lycopene. Lipid profile, antioxidant status, PSA, and IGF-1 were not modified by consumption of tomato pastes and lycopene. When prostate cancer cells were treated in vitro with sera collected from men after red tomato paste consumption, IGF binding protein-3 (IGFBP-3) and the ratio of Bax to Bcl2 were up regulated, and cyclin-D1, p53, and Nrf-2 were down regulated compared with expression levels obtained using sera taken after the first washout period. Intermediate gene expression changes were observed using sera collected from participants after consumption of yellow tomato paste with low carotenoid content. Cell incubation with sera from men who consumed purified lycopene led to significant up-regulation of IGFBP-3, c-fos, and uPAR compared with sera collected after placebo consumption. These findings suggest that lycopene may not be the only factor responsible for the cancer-protective effects of tomatoes.
In another study, the effect of tomato sauce on apoptosis in benign prostatic 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.
One study of 40 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 men 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 (6 of 20) than in men who had received lycopene (2 of 20). These findings suggest that lycopene may be effective in preventing HGPIN from progressing to prostate cancer. 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.  Another randomized placebo-controlled study of consumption of a lycopene-rich tomato extract that was taken for approximately 6 months in 58 men with HGPIN reported no discernible effect on cell proliferation or cell cycle inhibition in benign prostatic epithelium or in serum PSA levels, despite a substantial increase in serum lycopene.
In another study, 32 men with HGPIN received a lycopene-enriched diet (20-25 mg/day lycopene from triple-concentrated tomato paste) before undergoing a repeat biopsy after 6 months. No overall clinical benefit was seen in decreasing the rate of progression to prostate cancer. Baseline PSA levels showed no significant change. Prostatic lycopene concentration was the only difference between those whose repeat biopsy showed HGPIN, prostatitis, or prostate cancer. Prostatic lycopene concentration below 1 ng/mg was associated with prostate cancer at the 6-month follow-up biopsy (P = .003). Refer to the Multicomponent Therapies section of this summary for more information about trials of multicomponent therapies that include lycopene.
Other studies have examined the potential therapeutic effect of lycopene-containing products in men with prostate cancer. The effects of lycopene supplementation on prostate tissue and prostate cancer biomarkers were investigated in men with localized prostate cancer in a 2002 pilot study. Men received either lycopene supplements (30 mg/d) or no intervention twice daily for 3 weeks before radical prostatectomy. Men in the intervention arm had smaller tumors (80% vs. 45%, less than 4 ml), less involvement of surgical margins and/or extraprostatic tissues with cancer (73% vs. 18%, organ-confined disease), and less diffuse involvement of the prostate by HGPIN (33% vs. 0%, focal involvement) compared with men in the control group. Mean plasma PSA levels were lower in the intervention group compared with the control group. Refer to the Multicomponent Therapies section of this summary for more information on studies with lycopene.
In a phase II, randomized, placebo-controlled trial, 45 men with clinically localized prostate cancer received either 15, 30, or 45 mg of lycopene (Lyc-O-Mato) or no supplement from time of biopsy to prostatectomy (30 days). Plasma lycopene increased from baseline to the end of treatment in all treatment groups, with the greatest increase observed in the 45 mg lycopene-supplemented arm. No toxicity was reported. Overall, men with prostate cancer had lower baseline levels of plasma lycopene, compared with disease-free controls, and similar to levels observed in previous studies in men with prostate cancer.[51,52] At the 30 mg lycopene dose level, a moderate decrease in mean free testosterone and significant increases in mean plasma estradiol and in serum sex hormone-binding globulin (SHBG) (P = .022) were observed. At the 45 mg/d dose, serum total estradiol increased (P = .006) with no significant change in serum testosterone. However, serum testosterone and SHBG levels in the control group remained unchanged. The mean difference between groups who received the lycopene supplementation demonstrated a lower percentage of cells expressing Ki-67, compared with the control group. Notably, 75% of subjects in the 30 mg lycopene-supplemented arm had a decrease in the percentage of cells expressing Ki-67, compared with the subjects in the control group, in which 100% of the subjects observed an increase. These changes were not statistically significant, compared with the changes in the control arm for this sample size and duration of intervention. Although antioxidant properties of lycopene have been hypothesized to be primarily responsible for its beneficial effects, this study suggests that other mechanisms mediated by steroid hormones may also be involved.
In a single-arm study of previously untreated men diagnosed with localized prostate cancer, investigators determined whether PSA velocity was altered by a 1-year intervention with lycopene supplementation (10 mg/d). A statistically significant decrease in PSA velocity after lycopene treatment was observed (P = .0007). Analysis of the PSA-doubling time (pretreatment vs. post-treatment) showed a median increase after supplementation for 174 days; however, this was not statistically significant.
In one study, prostate cancer patients (N = 36) who had biochemical relapse following radiation therapy or surgery received lycopene supplements twice daily for 1 year. There were six cohorts in the study, each receiving a different dose of lycopene (15, 30, 45, 60, 90, or 120 mg/d). Serum PSA levels did not respond to lycopene treatment. Plasma lycopene levels rose and appeared to plateau by 3 months for all doses. The results indicate that, although lycopene may be safe and well tolerated, it did not alter serum PSA levels in biochemically relapsed prostate cancer patients.
In a 2004 open-label study, patients with hormone-refractory prostate cancer (HRPC) (N = 20) received lycopene supplements daily (10 mg/d of lycopene) for 3 months. Of the study's participants, 50% had PSA levels that remained stable, 15% showed biochemical progression, 30% showed a partial response, and one patient (5% of the total sample) exhibited a complete response after treatment. In a phase II study, HRPC patients took lycopene supplements daily (15 mg of lycopene/d) for 6 months. By the end of the study, serum PSA levels had almost doubled in 12 of the 17 patients, and 5 of 17 patients had achieved PSA stabilization. Although this was a small study without a control group, the results suggest that lycopene may not be beneficial for patients with advanced prostate cancer.
In another study, 46 patients with androgen-independent prostate cancer consumed either tomato paste or tomato juice daily (both preparations provided 30 mg of lycopene/d) for at least 4 months. Only one patient in this study exhibited a decrease in PSA level. Several episodes of gastrointestinal side effects were noted after eating the tomato paste or drinking the tomato juice.
On the basis of the available evidence, early randomized clinical trials with lycopene as a single agent, in tomato products, and in combination with other agents (fish oil supplements, tomato products plus selenium, omega-3 fatty acids, soy isoflavones, grape/pomegranate juice and green/black tea) demonstrates bioavailability in serum and modulation of intermediate biomarkers implicated in prostate carcinogenesis and prostate cancer progression in most studies. Perhaps, future clinical trials should include longer duration of consistent lycopene exposure, while accounting for variations in individual absorption of carotenoids and heterogeneity of high-risk (HGPIN, atypical small acinar proliferation) and prostate cancer patient populations (indolent vs. aggressive prostate cancer or androgen-dependent vs. androgen-independent prostate cancer).
Studies evaluating lycopene in randomized clinical trials targeting men at high risk for prostate cancer and populations with prostate cancer have indicated relatively few toxicities at the dose and duration of intervention.[38,40,41,46,49] Doses of lycopene ranging between 8 mg and 45 mg administered over a period ranging from 3 weeks to 2 years have been reported to be safe in randomized clinical trials targeting the prostate. When adverse effects occurred, they tended to present as gastrointestinal symptoms  and, in one study, the symptoms resolved when lycopene was taken with meals. Another study reported that one participant withdrew because of diarrhea.
The FDA has accepted the determination by various companies that their lycopene-containing products meet the FDA's requirements for the designation of GRAS.
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. CP is found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature. Modification results in shorter molecules that dissolve better in water and are more readily absorbed by the body than are complex, longer chain CPs. 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.
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.
MCP was also shown to activate natural killer cells in leukemic cell cultures, suggesting it may be able to stimulate the immune system.
Preclinical Studies/Animal Studies
In a 2007 study, pectins were investigated for their anticancer properties. Prostate cancer cells were treated with three different pectins; CP, Pectasol (PeS, a dietary supplement containing MCP), and fractionated pectin powder (FPP). FPP induced apoptosis to a much greater degree than did CP and PeS. Further analysis revealed that treating prostate cancer cells with heated CP resulted in levels of apoptosis similar to those following treatment with FPP. This suggests that specific structural features of pectin may be responsible for its ability to induce apoptosis in prostate cancer cells.
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.
In one study, the role of galectin-3, a multifunctional endogenous lectin, in cisplatin -treated prostate cancer cells was examined. Prostate cancer cells that expressed galectin-3 were found to be resistant to the apoptotic effects of cisplatin. However, cells that did not express galectin-3 (via silencing RNA knockdown of galectin-3 expression or treatment with MCP) were susceptible to cisplatin-induced apoptosis. These findings suggest that galectin-3 expression may play a role in prostate cancer cell chemoresistance and that the efficacy of cisplatin treatment in prostate cancer may be improved by inhibiting galectin-3.
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.
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.
The effect of MCP on prostate-specific antigen (PSA) doubling time (PSADT) was investigated in a 2003 study. Prostate cancer patients with rising PSA levels received six PeS capsules 3 times a day (totaling 14.4 g of MCP powder/d) for 12 months. Following treatment, 7 of 10 patients had a statistically significant (P ≤ .05) increase in PSADT.
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. 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.
The pomegranate tree (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, the East Indies, Africa, and the United States. 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. 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 minerals and a number of bioactive polyphenolic compounds, in particular structurally distinct ellagitannins and derivatives, such as alpha-/beta-punicalagin, punicalin, and punigluconin. The arils are mainly composed of water and also contain phenolics and flavonoids. Anthocyanins, which are flavonoids present in arils, are responsible for the red color of the fruit and its juice. The majority of antioxidant activity comes from ellagitannins. It has been shown that conversion of pomegranate ellagitannins by gut microbes produces a variety of metabolites, such as the urolithins.
Research studies suggest that pomegranates have beneficial effects on a number of health conditions, including cardiovascular disease, and may also have positive effects on oral or dental health.
Research studies in the laboratory have examined the effects of pomegranate on many prostate cancer cell lines and in rodent models of the disease.
Ellagitannins (the main polyphenols in pomegranate juice) are hydrolyzed to ellagic acid, and then to urolithin A (UA) derivatives. According to a tissue distribution experiment in wild-type mice, the prostate gland rapidly takes up high concentrations of UA after oral or intraperitoneal administration (0.3 mg/mouse/dose). Ellagic acid (EA) was detected in the prostate following intraperitoneal, but not oral, administration of pomegranate extract (0.8 mg/mouse/dose).
Treating human prostate cancer cells with individual components of the pomegranate fruit has been shown to inhibit cell growth.[9,10,11,12] In one study, dihydrotestosterone -stimulated LNCaP cells were treated with 13 pomegranate compounds at various concentrations (0-100 µM). Four of the 13 compounds, epigallocatechin gallate (EGCG), delphinidin chloride, kaempferol, and punicic acid, exhibited an ability to inhibit cell growth in a dose-dependent manner. Treating cells with EGCG, kaempferol, and punicic acid further resulted in apoptosis, with punicic acid (a major constituent of pomegranate seeds) being the strongest inducer of apoptosis. Additionally, findings from this study suggested that punicic acid may activate apoptosis by a caspase-dependent pathway.
Pomegranate extracts have also been shown to inhibit the proliferation of human prostate cancer cells in vitro.[11,13,14] In one study, three prostate cancer cell lines (LNCaP, LNCaP-AR, and DU-145) were treated with pomegranate polyphenols [punicalagin (PA) or EA], a pomegranate extract (POMx, which contains EA and PA), or pomegranate juice (PJ, which contains PA, EA, and anthocyanins) in concentrations ranging from 3.125 to 50 µg/mL (standardized to PA content). All four treatments resulted in statistically significant increases in apoptosis and dose-dependent decreases in cell proliferation in the three cell lines. However, PJ and POMx were stronger inhibitors of cell growth than were PA and EA. In this study, the effects of PA, EA, POMx, and PJ on the expression of androgen -synthesizing enzyme genes and the androgen receptor were also measured. Although statistically significant decreases in gene expression occurred in LNCaP cells following treatment with POMx and in DU-145 cells following treatment with EA and POMx, significant decreases in gene expression and androgen receptor occurred in LNCaP-AR cells following all of the treatments. In a second study, treating PC3 cells (human prostate cancer cells with a high metastatic potential) with POMx (10-100 µg/mL) resulted in cell growth inhibition and apoptosis, both in a dose-dependent manner. Treatment of CWR22Rv1 cells (prostate cancer cells that express the androgen receptor and secrete PSA) with POMx (10-100 µg/mL concentrations of pomegranate fruit extract) led to the inhibition of cell growth, a dose-dependent decrease in androgen receptor protein expression, and dose-dependent reductions in PSA protein levels.
The enzyme cytochrome P450 (CYP1B1) has been implicated in cancer development and progression. As a result, CYP1B1 inhibitors may be effective anticarcinogenic targets. In a study reported in 2009, the effects of pomegranate metabolites on CYP1B1 activation and expression in CWR22Rv1 prostate cancer cells were examined. In this study, urolithins A and B inhibited CYP1B1 expression and activity.
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.
In a study reported in 2011, human hormone -independent prostate cancer cells (DU145 and PC3 cell lines) were treated with 1% or 5% PJ for times ranging from 12 to 72 hours. The results showed that treatment with PJ increased adhesion and decreased the migration of prostate cancer cells. Molecular analyses revealed that PJ increased the expression of cell-adhesion related genes and inhibited the expression of genes involved in cytoskeletal function and cellular migration. These findings suggested that PJ may be beneficial in slowing down or preventing cancer cell metastasis. 
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. In other studies, treatment with a POMx resulted in decreased tumor volumes in SCID mice that had been injected with prostate cancer cells.[8,17]
Similarly, when nude mice were injected with pomegranate seed oil (2 µg/g body weight), pomegranate pericarp (peel) polyphenols (2 µg/g body weight), or saline 5 to 10 minutes before being implanted with solid prostate cancer tumors, mice injected with the pomegranate extracts had significantly smaller tumor volumes compared with the mice injected with saline (P < .001).
In a study reported in 2011, 6-week-old transgenic adenocarcinoma of the mouse prostate (TRAMP) mice received normal drinking water or PJ (0.1% or 0.2% POMx in drinking water) for 28 weeks. The results showed that 100% of the mice that received water only developed tumors by age 20 weeks, whereas just 30% and 20% of the mice that received 0.1% and 0.2% PJ, respectively, developed tumors. By age 34 weeks, 90% of the water-fed mice exhibited metastases to distant organs whereas only 20% of the mice that received pomegranate juice showed metastasis. The PJ-supplemented mice exhibited significantly increased life spans compared with the water-fed mice.
Three clinical studies have examined the effect of interventions with pomegranate products on changes in PSADT in patients with biochemically recurrent prostate cancer who had a rising PSA after surgery or radiation therapy for presumed localized cancer. The first study was a single-arm trial of 48 patients who drank 8 ounces (570 mg/d total polyphenol gallic acid equivalents) of PJ for up to 33 months. PSADT rose from a mean of 15 months (±11 months) at baseline to a mean of 54 months (±102 months, P < .001) on treatment (with a twofold increase in median PSADT from 11.8 to 24 months, P = .029).
The second phase II study was published in 2013 and randomly assigned 92 patients to either 1 g (polyphenol gallic acid content equivalent to 8 ounces of pomegranate juice [47 patients]) or 3 g (45 patients) of pomegranate extract powder for up to 18 months. Overall, median PSADT increased from 11.9 to 18.5 months (P < .001), but no dose effect was seen (P = .554). Median PSADT increased from 11.9 to 18.8 months in the low-dose arm and from 12.2 to 17.5 months in the high-dose arm.
The third trial was a randomized, double-blinded, placebo controlled study published in 2015. Of the 183 patients who enrolled, 64 patients were treated with placebo, 17 patients were treated with PJ, and 102 patients were treated with pomegranate liquid extract, which contained the same compounds found in PJ, with the exception of a higher proportional content of pomegranate polyphenol and a lower anthocyanidin content. The median change in PSADT was 4.5 months for the placebo group, 1.6 months for the extract group, and 7.6 months for the juice group; however, no paired comparison of groups was statistically significant.
The differences in results between the trials may be partly because of less aggressive disease in the 2006 patient population with lower starting PSA values, but may also be because the first two trials lacked a placebo arm. All three trials found that pomegranate extract was safe to consume. Of note, in both the 2006 and 2013 studies, two patients in each trial had a 50% decline in PSA. In light of these findings, researchers wondered if there may be a sensitive subpopulation that might benefit from PJ. One potential genetic biomarker candidate is manganese superoxide dismutase (MnSOD), which is the primary antioxidant enzyme in mitochondria. A polymorphism at codon 16 of the MnSOD gene in men encodes either alanine (A) or valine (V). The AA genotype has been associated with more aggressive prostate cancer and with more sensitivity to antioxidants than the VA or VV genotype. A preplanned subset analysis in the 2015 study of the 34 (22%) men with MnSOD AA genotype demonstrated a greater PSADT lengthening in the liquid extract group (median PSADT increased from 13.6 months to 25.6 months, P = .03) while no significant change was seen in the placebo group of MnSOD (median PSADT increased from 10.9-12.7 months, P = .22). In summary, the finding that men with the AA genotype who received pomegranate extract had greater lengthening of PSADT than did men in the placebo arm, along with the safe profile of PJ and extract in three large studies, suggest that there may be benefit in further studies in the AA MnSOD subpopulation.
In a study of prostate cancer patients reported in 2006, the PJ intervention was well tolerated and no serious adverse effects were observed.
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.
Selenium is an essential trace mineral involved in a number of biological processes, including enzyme regulation, gene expression, and immune function. Selenium was discovered in 1818 and named after the Greek goddess of the moon, Selene. A number of selenoproteins have been identified in humans, including selenoprotein P (SEPP), which is the main selenium carrier in the body and is important for selenium homeostasis.
Food sources of selenium include meat, vegetables, and nuts. The selenium content of the soil where food is raised determines the amount of selenium found in plants and animals. For adults, the recommended daily allowance for selenium is 55 µg. Most dietary selenium occurs as selenocysteine or selenomethionine. Selenium accumulates in the thyroid gland, liver, pancreas, pituitary gland, and renal medulla.
Selenium is a component of the enzyme glutathione peroxidase, an enzyme that functions as an antioxidant. However, at high concentrations, selenium may function as a pro-oxidant.
Selenium is implicated in a number of disease states. Selenium deficiency may result in Keshan disease, a form of childhood cardiomyopathy, and Kaskin-Beck disease, a bone disorder. Some clinical trials have suggested that high levels of selenium may be associated with diabetes  and high cholesterol.
Selenium may also play a role in cancer. Animal and epidemiological studies have suggested there may be an inverse relationship between selenium supplementation and cancer risk. The Nutritional Prevention of Cancer Trial (NPC) was a randomized, placebo-controlled study designed to test the hypothesis that higher selenium levels were associated with lower incidence of skin cancer. The results indicated that selenium supplementation did not affect risk of skin cancer, although incidences of lung, colorectal, and prostate cancer were significantly reduced.
There is evidence that selenoproteins may be associated with carcinogenesis. For example, reduced expression of glutathione peroxidase 3 and SEPP have been observed in some tumors, while increased expression of glutathione peroxidase 2 occurs in colorectal and lung tumors.
Different selenium-containing compounds have variable effects on prostate cancer cells as well as normal cells and tissues. Both naturally occurring and synthetic organic forms of selenium have been shown to decrease the growth and function of prostate cancer cells. In a 2011 study, prostate cancer cells were treated with various forms of selenium; selenite and methylseleninic acid (MSeA) had the greatest cytotoxic effects.
Studies have suggested that selenium nanoparticles may be less toxic to normal tissues than are other selenium compounds. One study investigated the effects of selenium nanoparticles on prostate cancer cells. The treated cells had decreased activity of the androgen receptor, which led to apoptosis and growth inhibition.
In a 2010 study, prostate cancer cells treated with sodium selenite (a natural form of selenium) exhibited increased levels of p53 (a tumor suppressor). Findings also revealed that p53 may play a key role in selenium-induced apoptosis.
In a second study, the prostate cancer cell line LNCaP was modified to separately overexpress each of four antioxidant enzymes. Cells from the modified cell line were then treated with sodium selenite. The cells overexpressing manganese superoxide dismutase (MnSOD) were the only ones able to suppress selenite-induced apoptosis. These findings suggest that superoxide production in mitochondria may be important in selenium-induced apoptosis occurring in prostate cancer cells and that levels of MnSOD in cancer cells may determine the effectiveness of selenium in inhibiting those cells.
One study treated prostate cancer cells and benign prostatic hyperplasia (BPH) cells with sodium selenite. Growth of LNCaP cells was stimulated by noncytotoxic, low concentrations of sodium selenite; while growth inhibition occurred in PC-3 cells at these concentrations-prompting the authors to suggest that selenium may be beneficial in advanced prostate cancer-selenium supplementation may have adverse effects in hormone-sensitive prostate cancer. However, the relevance of these findings to the clinical setting is unclear. These experiments used selenium concentrations of 1 to 10 µg/mL, whereas the average U.S. adult male serum selenium concentrations are about 0.125 µg/mL, and prostate tissue concentrations are about 1.5 µg/g.
A 2012 study investigated whether various forms of selenium (i.e., SeMet and selenium-enriched yeast [Se-yeast]) differentially affect biomarkers in the prostate. Elderly dogs received nutritionally adequate or supranutritional levels of selenium in the form of SeMet or Se-yeast. Both types of selenium supplementation increased selenium levels in toenails and prostate tissue to a similar degree. The different forms of selenium supplementation showed no significant differences in DNA damage, proliferation, or apoptosis in the prostate.
At least one study has compared these three forms of selenium in athymic nude mice injected with human prostate cancer cells and found that MSeA was more effective in inhibiting tumor growth than was SeMet or selenite. Another study investigated the effect of age on selenium chemoprevention in mice. Mice were fed selenium-depleted or selenium-containing (at nutritional or supranutritional levels) diets for 6 months or 4 weeks and were then injected with PC-3 prostate cancer cells. Adult mice that were fed selenium-containing diets exhibited fewer tumors than did adult mice fed selenium-depleted diets. In adult mice, selenium-depleted diets resulted in tumors with more necrosis and inflammation compared with selenium-containing diets. However, in young mice, tumor development and histopathology were not affected by dietary selenium.
The effects of MSeA and methylselenocysteine (MSeC) have also been explored in a transgenic model of in situ murine prostate cancer development, the TRAMP mouse. Treatment with MSeA and MSeC resulted in slower progression of prostatic intraepithelial neoplasia (PIN) lesions, decreased cell proliferation, and increased apoptosis compared with treatment with water. MSeA treatment also increased survival time of TRAMP mice. TRAMP mice that received MSeA treatment starting at age 10 weeks exhibited less aggressive prostate cancer than did mice that started treatment at 16 weeks, suggesting early intervention with MSeA may be more effective than later treatment. The same research group later investigated some of the cellular mechanisms responsible for the different effects of MSeA and MSeC. MSeA and MSeC were shown to affect proteins involved in different cellular pathways. MSeA mainly affected proteins related to prostate differentiation, androgen receptor signaling, protein folding, and endoplasmic reticulum-stress responses, whereas MSeC affected enzymes involved in phase II detoxification or cytoprotection. One study suggested that MSeA may inhibit cell growth and increase apoptosis by inactivating PKC isoenzymes.
The results of epidemiological studies suggest some complexity in the association between the blood levels of selenium and the risk of acquiring prostate cancer. As part of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg study, men completed dietary questionnaires, had blood samples taken, and were monitored every 2 to 3 years for up to 10 years. The findings revealed a significantly decreased risk of prostate cancer for individuals with higher blood selenium concentrations. In a prospective pilot study, prostate cancer patients had significantly lower whole blood selenium levels than did healthy males. However, in a 2009 study of prostate cancer patients, men with higher plasma selenium levels were at greater risk of being diagnosed with aggressive prostate cancer.
Various molecular pathways have been explored to better understand the association between blood selenium levels and the development of prostate cancer. In the EPIC-Heidelberg study, polymorphisms in the selenium-containing enzymes GPX1 and SEP15 genes were found to be associated with prostate cancer risk. Another study that used DNA samples obtained from the EPIC-Heidelberg study suggested that prostate cancer risk may be associated with single nucleotide polymorphisms (SNPs) in thioredoxin reductase and selenoprotein K genes along with selenium status. A 2012 study investigated associations between variants in selenoenzyme genes and risk of prostate cancer and prostate cancer-specific mortality. Among SNPs analyzed, only GPX1 rs3448 was related to overall prostate cancer risk.
A retrospective analysis of prostate cancer patients and healthy controls showed an association between aggressive prostate cancer and decreased selenium and SEPP status. In the Physicians' Health Study, links between SNPs in the SEPP gene (SEPP1) and prostate cancer risk and survival were examined. Two SNPs were significantly associated with prostate cancer incidence: rs11959466 was associated with increased risk, and rs13168440 was associated with decreased risk. Tumor SEPP1 mRNA expression levels were lower in men with lethal prostate cancer than in men with nonlethal prostate cancer. In one study, the direction of the association between blood selenium levels and advanced prostate cancer incidence differed according to which of two polymorphisms a patient had for the gene encoding the enzyme MnSOD. For men with the alanine-alanine (AA) genotype, higher selenium levels were associated with a reduced risk of presenting with aggressive disease, whereas the opposite was seen among men with a valine (V) allele.
An analysis of 4,459 men in the Health Professionals Follow-Up Study who were initially diagnosed with prostate cancer found that selenium supplementation of 140 μg or more per day after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality. The authors recommended caution in the use of selenium supplements among men with prostate cancer. Risk of prostate cancer mortality rose at all levels of selenium consumption. Men who consumed 1 to 24 μg/day, 25 to 139 μg/day, and 140 μg/day or more of supplemental selenium had a 1.18-fold (95% confidence interval [CI], 0.73-1.91), 1.33-fold (95% CI, 0.77-2.30), and 2.60-fold (95% CI, 1.44-4.70) increased prostate cancer mortality risk compared with nonusers, respectively (Ptrend = .001). The authors reported no statistically significant association between selenium supplement use and biochemical recurrence, cardiovascular disease mortality, or overall mortality.
Sixty adult males were randomly assigned to receive either a daily placebo or 200 µg of selenium glycinate supplements for 6 weeks. Blood samples were collected at the start and end of the study. Compared with the placebo group, men who received selenium supplements exhibited significantly increased activity of two blood selenium enzymes and significantly decreased levels of prostate-specific antigen (PSA) at the end of the study.
A meta-analysis published in 2012 reviewed human studies that investigated links between selenium intake, selenium status, and prostate cancer risk. The results suggested an association between decreased prostate cancer risk and a narrow range of selenium status (plasma selenium concentrations up to 170 ng/mL and toenail selenium concentrations between 0.85 and 0.94 µg/g).
In another study, prostate cancer patients were randomly assigned to receive either combination silymarin (570 mg) and selenomethionine (240 µg) supplement or placebo daily for 6 months following radical prostatectomy. While there was no change in PSA levels between the groups after 6 months, the participants receiving supplements reported improved quality of life and showed decreases in low-density lipoprotein cholesterol and total cholesterol.
In one study, 140 prostate cancer patients undergoing active surveillance were randomly assigned to receive low-dose selenium (200 µg/d), high-dose selenium (800 µg/d), or placebo daily for up to 5 years. Selenium was given in the form of Se-yeast. Men receiving the high-dose selenium, and who had the highest baseline plasma selenium levels, had a higher PSA velocity than did men in the placebo group. There was not a significant effect of selenium supplements on PSA velocity in men who had lower baseline levels of selenium.
In 2013, results of a phase III randomized, placebo-controlled trial investigating the effect of selenium supplementation on prostate cancer incidence in men at high risk for the disease were reported. Subjects (N = 699) were randomly assigned to receive either daily placebo or one of two doses of high-Se-yeast (200 µg/d or 400 µg/d). They were monitored every 6 months, up to 5 years. Compared with placebo, selenium supplementation had no effect on prostate cancer incidence or PSA velocity. In an earlier study, men with HGPIN were randomly assigned to receive either placebo or 200 µg of selenium daily for 3 years or until prostate cancer diagnosis. The results suggested that selenium supplementation had no effect on prostate cancer risk.
The Selenium and Vitamin E Cancer Prevention Trial (SELECT)
On the basis of findings from earlier studies,[8,37] the SELECT, a large multicenter clinical trial, was initiated by the National Institutes of Health in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer. SELECT was a phase III, randomized, double-blind, placebo-controlled, population-based trial. More than 35,000 men, aged 50 years or older, from more than 400 study sites in the United States, Canada, and Puerto Rico, were randomly assigned to receive vitamin E (alpha-tocopherol acetate, 400 IU /d) and a placebo, selenium (L-selenomethionine, 200 µg/d) and a placebo, vitamin E and selenium, or two placebos daily for 7 to 12 years. The primary endpoint of the clinical trial was incidence of prostate cancer.
Initial results of SELECT were published in 2009. There were no statistically significant differences in rates of prostate cancer in the four groups. In the vitamin E-alone group, there was a nonsignificant increase in rates of prostate cancer (P = .06); in the selenium-alone group, there was a nonsignificant increase in incidence of diabetes mellitus (P = .16). On the basis of those findings, the data and safety monitoring committee recommended that participants stop taking the study supplements.
Updated results were published in 2011. When compared with the placebo group, the rate of prostate cancer detection was significantly greater in the vitamin E-alone group (P = .008) and represented a 17% increase in prostate cancer risk. There was also greater incidence of prostate cancer in men who had taken selenium than in men who took placebo, but those differences were not statistically significant.
A number of explanations have been suggested, including the dose and form of vitamin E that was used in the trial as well as the specific form of selenium chosen for the study. L-selenomethionine was used in SELECT, while selenite and Se-yeast had been used in previous studies. SELECT researchers chose selenomethionine because it was the major component of Se-yeast and because selenite was not absorbed well by the body, resulting in lower selenium stores. In addition, there were concerns about product consistency with high-Se-yeast. However, selenomethionine is involved in general protein synthesis and can have numerous metabolites such as methylselenol, which may have antitumor properties.[43,44]
Toenail selenium concentrations were examined in two-case cohort subset studies of SELECT participants. Total selenium concentration in the absence of supplementation was not associated with prostate cancer risk. Selenium supplementation in SELECT had no effect on prostate cancer risk among men with low selenium status at baseline but increased the risk of high-grade prostate cancer in men with higher baseline selenium status by 91% (P = .007). The authors concluded that men should avoid selenium supplementation at doses exceeding recommended dietary intakes. An international collaboration compiled and reanalyzed data from 15 studies that investigated the association between blood and toenail selenium concentrations and prostate cancer risk. In the analysis of 6,497 men with prostate cancer and 8,107 controls, blood selenium level was not associated with the risk of total prostate cancer, but high blood selenium level was associated with a lower risk of aggressive disease. Toenail selenium concentration was inversely associated with risk of total prostate cancer (odds ratio, 0.29; 95% CI, 0.22-0.40; Ptrend < .001), including both aggressive and nonaggressive disease.
In a case-cohort analysis of 1,434 men in the SELECT who underwent analysis of SNPs in 21 genes, investigators found support for the hypothesis that genetic variation in selenium and vitamin E metabolism/transport genes may influence the risk of overall and high-grade prostate cancer and that selenium or vitamin E supplementation may modify an individual's response to those risks.
Selenium supplementation was well tolerated in many clinical trials. In two published trials, there were no differences reported in adverse effects between placebo or treatment groups.[34,35] However, in SELECT, selenium supplementation was associated with a nonsignificant increase in incidence of diabetes mellitus (P = .08).
General Information & History
Although records of soy use in China date back to the 11th 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.
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. Other isoflavones found in soy include daidzein and glycitein. Isoflavones help soybeans survive in times of stress and have antioxidant, antimicrobial, and antifungal properties.
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 after soy product consumption. Isoflavones are phytoestrogens (they bind to estrogen receptors) with a greater binding affinity for estrogen receptor beta than for estrogen receptor alpha.
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. Subsequently, genistein was found to inhibit multiple protein tyrosine kinases relevant to cancer cell proliferation. In addition, numerous studies have shown that prostate cancer incidence is very low in Asian countries, where diets tend to be high in soy.
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. In another study, human prostate cancer cells were treated with genistein or daidzein. The isoflavones were shown to down regulate growth factors involved in angiogenesis (e.g., EGF and IGF-1) and the interleukin -8 gene, which is associated with cancer progression. These findings suggest that genistein and daidzein may have chemopreventive properties. Both genistein and daidzein have been shown to reduce the proliferation of LNCaP and PC-3 prostate cancer cells in vitro. However, during the 72 hours of incubation, only genistein provoked effects on the dynamic phenotype and decreased invasiveness in PC-3 cells. These results imply that invasive activity is at least partially dependent on membrane fluidity and that genistein may exert its antimetastatic effects by changing the mechanical properties of prostate cancer cells. No such effects were observed for daidzein at the same dose.
Combinations of isoflavones
Some experiments have compared the effects of individual isoflavones with isoflavone combinations on prostate cancer cells. In one 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 suggested that products containing a combination of active compounds (e.g., whole foods) may be more effective in preventing cancer than individual compounds. 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.
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.
Animal models of prostate cancer have been used in studies investigating the effects of soy and isoflavones on the disease. Wild-type and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control diets or diets containing genistein (250 mg genistein/kg chow). The TRAMP mice fed with genistein exhibited reduced cell proliferation in the prostate compared with TRAMP mice fed a control diet. The genistein-supplemented diet also reduced levels of ERK-1 and ERK-2 (proteins important in stimulating cell proliferation) as well as the growth factor receptors EGFR and IGF-1R in TRAMP mice, suggesting that down regulation of these proteins may be one mechanism by which genistein exerts chemopreventive effects. In one study, following the appearance of spontaneous prostatic intraepithelial neoplasia lesions, TRAMP mice were fed control diets or diets supplemented with genistein (250 or 1,000 mg genistein/kg chow). Mice fed low-dose genistein exhibited more cancer cell metastasis and greater osteopontin expression than mice fed the control or the high-dose genistein diet. These results indicate that timing and dose of genistein treatment may affect prostate cancer outcomes and that genistein may exert biphasic control over prostate cancer. 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. 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/d) or peanut oil vehicle by gavage. In addition, there was a reduction in tumor cell apoptosis in the genistein-treated mice compared with the vehicle-treated mice. These findings suggest that genistein may stimulate metastasis in an animal model of advanced prostate cancer.
Radiation therapy is commonly used in prostate cancer, but, despite this treatment, disease recurrence is common. Therefore, combining radiation with additional therapies may provide longer-lasting results. In one study, human prostate cancer cells were treated with soy isoflavones and/or radiation. Cells that were treated with both isoflavones and radiation exhibited greater decreases in cell survival and greater expression of proapoptotic molecules than cells treated with isoflavones or radiation only. Nude mice were implanted with prostate cancer cells and treated by gavage with genistein (21.5 mg/kg body weight/d), mixed isoflavones (50 mg/kg body weight/d; contained 43% genistein, 21% daidzein, and 2% glycitein) and/or radiation. Mixed isoflavones were more effective than genistein in inhibiting prostate tumor growth, and combining isoflavones with radiation resulted in the largest inhibition of tumor growth. In addition, mice given soy isoflavones in combination with radiation did not exhibit lymph node metastasis, which was seen previously in other experiments combining genistein with radiation. These preclinical findings suggest that mixed isoflavones may increase the efficacy of radiation therapy for prostate cancer.
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.
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. An updated 2013 meta-analysis confirmed the good safety profile of isoflavones but indicated no significant differences between treated and control groups for PSA levels or sex steroid endpoints (sex hormone-binding globulin, testosterone, free testosterone, estradiol, and dihydrotestosterone). One study assessed urinary concentrations of phytoestrogens in healthy Jamaican men and men newly diagnosed with prostate cancer. There were no differences in urinary concentrations of the isoflavones genistein and daidzein between healthy men and prostate cancer patients. Men who produced equol (a metabolite of daidzein) were at a lower risk of prostate cancer than men who were nonproducers.
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; comprising 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).
Although soy is a standard part of many Asian diets, it is less common in Western diets. Therefore, feasibility studies were undertaken to investigate whether Western participants would adhere to soy-supplementation interventions. In one study, healthy men were randomly assigned to consume a low-soy (usual diet) or high-soy (soy servings bid) 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.
In one study, men at risk of prostate cancer or with low-grade prostate cancer received one of three types of protein isolate (soy protein, alcohol-washed soy protein [a common method of producing soy protein concentrate that results in some loss of isoflavones], or milk protein) for 6 months. The isoflavone content of the interventions was 107±5.0 mg/d for soy protein isolate (containing 53% genistein, 35% daidzein, and 11% glycitein), <6±0.7 mg/d 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.
Japanese men who had serum PSA levels between 2.5 ng/mL and 10 ng/mL and a previous negative biopsy within 12 months were randomly assigned to receive either oral isoflavone (60 mg/d) or placebo for 12 months. One hundred fifty-eight men were enrolled with a median age of 66 years. There were no differences in PSA values or in incidence of biopsy-detectable prostate cancer before and after treatment in the isoflavone or placebo groups. In a subset analysis of the 53 men older than 65 years, 7 of 25 men in the isoflavone group developed prostate cancer, compared with 16 of 28 men in the placebo group (P = .031).
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/d; which contained the isoflavones genistein, daidzein, formononetin, and biochanin A) and were followed up for 1 year. After 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.
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.
In one small (n = 20), open-label study, patients with rising PSA levels following previous therapy consumed soy milk three times a day (isoflavonoid, 141 mg/d) 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.
In another study, prostate cancer patients received genistein-rich supplements (genistein, 450 mg/d, plus other aglycone isoflavones, 450 mg/d) 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%. 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.
In a study reported in 2011, prostate cancer patients scheduled for radical prostatectomy were randomly assigned to receive a placebo or 30 mg genistein daily for 3 to 6 weeks before surgery. Among the patients who received genistein, serum PSA levels decreased by 7.8%, whereas serum PSA levels increased by 4.4% in patients who received the placebo; this difference approached statistical significance (P = .051). In addition, the genistein intervention resulted in significantly lower levels of total cholesterol compared with placebo treatment (P = .013). Another group, however, conducted a randomized placebo-controlled trial to examine the effect of soy isoflavone capsules (total isoflavones, 80 mg/d) on localized prostate cancer in 86 men who took the capsules for up to 6 weeks before prostatectomy. Changes in serum-free and total testosterone, PSA, and total cholesterol were not different between the two groups. The investigators noted that the 12 genes involved in cell cycle control and the 9 genes involved in apoptosis were down regulated in the tumor tissues of the isoflavone-treated men, compared with the controls.
In a phase II, randomized, double-blind, placebo-controlled trial [34,35] of men with localized prostate cancer (Gleason score 2-6) who were administered isoflavones (80 mg/d) 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 were inversely correlated with changes in serum PSA, compared with the placebo arm.
In a second phase II, multidose, randomized placebo-controlled trial,[34,36] 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.
In one study, early-stage prostate cancer patients were randomly assigned to receive a soy protein supplement (isoflavones, 60 mg/d) 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.
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/d; each tablet contained 10.6 mg genistein, 13.3 mg daidzein, and 3.2 mg glycitein) or a placebo for 2 weeks before surgery. The isoflavone concentration in prostatic tissue was sixfold higher than in serum following treatment with the soy supplements, suggesting that the prostate may accumulate potentially anticarcinogenic levels of isoflavones. In another study, prostate cancer patients scheduled for radical prostatectomy were instructed to eat bread containing high levels of phytoestrogens (soy or soy + linseed; isoflavones, 117 mg/d) 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.
In a 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.
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. Two studies have examined men undergoing androgen deprivation therapy who were randomly assigned to receive a placebo or an isoflavone supplement (soy protein powder mixed with beverages; isoflavones, 160 mg/d) for 12 weeks. Neither study found an improvement in side effects following isoflavone treatment, compared with placebo treatment.[41,42]
Effects on inflammatory parameters
In a study of men undergoing androgen deprivation therapy, participants were randomly assigned to receive high-dose isoflavone supplements (providing total isoflavones, 160 mg/d 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).
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 isoflavones, 81.6 mg/d) 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.
Overall, soy was well tolerated in clinical studies of prostate cancer patients.[24,27,29,31,38,41] The most commonly reported side effects were gastrointestinal symptoms.[28,30,31] In addition, one study reported that a participant withdrew due to insomnia.
Vitamin D, also called calciferol, cholecalciferol (D3), or ergocalciferol (D2), is a fat-soluble vitamin found in fatty fish, fish liver oil, eggs, and fortified dairy products. Vitamin D is made naturally by the body when exposed to sunlight.
In 1922, researchers discovered that heated, oxidized cod-liver oil, called fat-soluble factor A and later known as vitamin D, played an important role in curing rickets in rats.
Vitamin D performs many roles in the body, including the following:
Vitamin D is needed for bone growth and protects against osteoporosis in adults. Vitamin D status is usually checked by measuring the level of 25-hydroxyvitamin D in the blood.
To study the role of vitamin D in cancer cell adhesion to endothelium, one study developed a microtube system that simulates the microvasculature of bone marrow. The study reported that 1,25-alpha-dihydroxyvitamin D3 (1,25-D3) suppressed adhesion of prostate cancer cells in the microtube system. In addition, it was shown that 1,25-D3 increased E-cadherin expression, which may prevent prostate cancer cell adhesion to endothelium by promoting cancer cell aggregation.
Vitamin D-binding protein (VDBP) transports vitamin D in the bloodstream. Studies have shown that one of its products, VDBP-macrophage activating factor (VDBP-maf), may have antiangiogenic and antitumor activities. One study examined the effects of VDBP-maf on prostate cancer cells. Treating prostate cancer cells with VDBP-maf resulted in inhibited cellular migration, proliferation, and reduced levels of urokinase plasminogen activator receptor (uPAR; activity of this receptor correlates with tumor metastasis). These findings suggest that VDBP-maf has a direct effect on prostate cancer cells.
Studies have reported that 1,25-D3 may play an important role in prostate cancer biology. Studies have suggested that a newly discovered protein, protein disulfide isomerase family A, member 3 (PDIA3), may function as a membrane receptor binding to 1,25-D3. According to one study, PDIA3 is expressed in normal prostate cells as well as in LNCaP and PC-3 prostate cancer cell lines. In addition, their findings suggest that 1,25-D3 may act on prostate cancer cells via multiple signaling pathways, indicating there may be a number of potential therapeutic targets.
Tumor progression was compared in two murine models of prostate cancer. In vitamin D receptor- knockout animals, rate of tumor progression and cellular proliferation were greater than in wild type animals. However, in mice that were supplemented with testosterone, these differences did not occur, suggesting that there may be significant interaction between androgen signaling and vitamin D signaling.
In a 2011 study, nude mice were fed a control diet or a diet deficient in vitamin D and were then injected with prostate cancer cells into bone marrow or into soft tissues. Osteolytic lesions were larger and progressed at a faster rate in vitamin D-deficient mice that had bone marrow injected with cancer cells than in mice that had adequate levels of vitamin D. However, there was no difference in soft tissue tumors among mice with different vitamin D levels. Results of this study show that vitamin D deficiency is associated with growth of prostate cancer cells in bone but not in soft tissue.
A 2014 study evaluated calcitriol and a less-calcemic vitamin D analog in an aggressive transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Neither vitamin D analog impacted the rate of development of castration -resistant prostate cancer in mice, whether they were treated before or after castration. However, both vitamin D analogs slowed progression of primary tumors in hormone-intact mice but enhanced distant organ metastases after prolonged treatment. In sum, intervention with potent vitamin D compounds in TRAMP mice slowed androgen-stimulated tumor progression but, over time, may have led to more aggressive disease as indicated by increased distant metastases (P = .0823). This preclinical data supports findings of the 2008 retrospective study  of an association between serum vitamin D levels and aggressive prostate cancer (refer to the Human Studies section in the Vitamin D section of this summary for more information about this study).
Vitamin D as adjuvant therapy
Cryotherapy may be used for treating prostate cancer. Studies have been conducted to identify potential agents that may help improve efficacy of the freezing procedure. In a 2010 study, mice were injected with prostate cancer cells and treated with calcitriol, cryoablation, or both. The combination treatment group experienced larger necrotic areas, more apoptosis, and less cell proliferation than did the other experimental groups. A subsequent study corroborated these findings, showing that combining calcitriol and cryoablation resulted in more cell death than cryotherapy alone.
Vitamin D may help enhance other types of cancer treatments, such as radiation. In another study, prostate cancer cells were treated with valproic acid (VPA) and/or 1,25-D3, followed by radiation. Cells that were treated with VPA and/or 1,25-D3 and radiation had greater decreases in cell proliferation than did cells treated solely with radiation. The greatest reduction in cell proliferation occurred in cells treated with VPA, 1,25-D3, and radiation.
The relationship between vitamin D and prostate cancer has been examined in numerous epidemiological studies. Vitamin D levels were analyzed annually for 5 years in patients with nonmetastatic prostate cancer. Results showed that throughout the course of the study, vitamin D insufficiency was prevalent among these cancer patients. Levels of vitamin D metabolites in prostate cancer patients were examined in a 2011 study. Analysis revealed that patients with the lowest concentrations of prediagnostic plasma 25-hydroxy vitamin D [25(OH)D] levels had a higher risk of developing metastatic prostate cancer than did patients with higher levels of 25(OH)D. However, there was no association between metastatic prostate cancer and circulating levels of 1,25(OH)D. In another study, serum levels of 25(OH)D in prostate cancer patients were assessed. Results suggest that medium or high levels of serum 25(OH)D may be associated with better prognoses than lower levels of serum 25(OH)D. These findings indicate that 25(OH)D may play a role in disease progression and may be a marker of prognosis in prostate cancer patients. Participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study who had been diagnosed with prostate cancer and control participants were selected for analysis and monitored for up to 20 years. Results suggested that men with a higher vitamin D status (assessed via serum 25(OH)D concentrations) had a greater risk of developing prostate cancer than did men with lower vitamin D status. A 2008 retrospective study of 749 men with prostate cancer diagnosed 1 to 8 years after blood draw and 781 matched controls found higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease. Both of these studies [9,16] were included in a meta-analysis of 21 studies, involving 11,941 cases and 13,870 controls, that found a 17% elevated risk of prostate cancer in men with higher levels of 25(OH)D. One explanation offered for this finding may be a potential detection bias with men from higher socio-economic groups who have higher vitamin D levels and who are more likely to undergo prostate-specific antigen (PSA) testing, resulting in higher reported incidence rates.
In one case-control study of men who had undergone prostate biopsies, men who had lower vitamin D levels before biopsy were more likely to have cancer detected at biopsy than did men whose prebiopsy vitamin D levels were not lower. Serum 25(OH)D levels were obtained from 667 men in Chicago undergoing first prostate biopsy for an elevated PSA or an abnormal digital rectal exam. Severe vitamin D deficiency (<12 ng /mL) was associated with increased risk of a prostate cancer diagnosis on biopsy among African American men. Severe deficiency was positively associated with higher Gleason score (≥4+4), higher clinical stage (>cT2b), and overall risk category in both white American and African American men. In contrast, baseline serum 25(OH)D levels obtained in a case (n = 1,731)-cohort (n = 3,203) analysis from the Selenium and Vitamin E Cancer Prevention Trial found significantly reduced risks among men who had moderate concentrations (45-70 nmol/L) compared with men who had lower or higher values. This U-shaped association was most pronounced for cancers with Gleason scores of 7 to 10. One hundred ninety men who participated in a large epidemiologic study underwent radical prostatectomy for clinically localized prostate cancer. At the time of prostatectomy, 87 men (45.8%) exhibited adverse pathology, defined as primary Gleason 4, any Gleason 5 or extraprostatic extension. Men with adverse pathology had lower median serum 25(OH)D (22.7 ng/mL), compared with their counterparts (27.0 ng/mL), and were also more likely to have a serum 25(OH)D level less than 30 ng/mL.
An important means of obtaining vitamin D is via sunlight. Studies have investigated the potential link between sunlight exposure and prostate cancer. According to a 2006 study, PSA levels rise at a slower rate during spring and summer than at other times of the year; this may be related to higher vitamin D levels obtained during those months. One study found that while men with low levels of sun exposure had increased risk of all prostate cancers, among men with prostate cancer, less sun exposure was associated with lower risk of advanced disease. Results of a meta-analysis, published in the same report, showed that men with low sun exposure had an increased risk of incident and advanced prostate cancer. Analysis of mortality rate data from 1950 to 1994 revealed that the geographic distribution of prostate cancer mortality in the United States is inversely related to UV radiation. In addition, this relationship is more evident in areas north of 40 degrees N latitude. Likewise, a study in France reported that UV radiation may be associated with reductions in cancer risk and mortality.
A number of studies have explored a possible connection between the vitamin D receptor (VDR) and risk of prostate cancer. A 2011 prospective study examined VDR expression in prostate tumors. Patients with high levels of VDR expression had lower PSA at diagnosis, less advanced tumor stage, and reduced risk of lethal prostate cancer compared with patients with lower levels of VDR expression in tumors. In a 2009 study, genetic variants in VDR were analyzed in prostate cancer patients participating in the Prostate Testing for Cancer and Treatment (ProtecT) trial. Five polymorphisms of VDR were identified in the participants. A meta-analysis, published in the same report, revealed no association between specific variants and prostate cancer stage (TNM staging system), but found that three genotypes (BSML, APAL, and TAQL) may be associated with cancer grade (Gleason score), suggesting there may be a link between specific VDR polymorphisms and advanced prostate cancer at diagnosis. Polymorphisms in the VDR receptor, the vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1) were examined in a 2010 study. Variations in the three genes investigated were associated with changes in risk of recurrence and progression of prostate cancer as well as prostate cancer mortality. A case-control study analyzed the correlation between VDBP single nucleotide polymorphisms (SNPs) and prostate cancer risk. Two SNPs in VDBP were associated with increased prostate cancer risk and high Gleason grade. However in another large cohort-consortium study, statistically significant association was not observed for either 25(OH)D or vitamin D-related SNPs with fatal prostate cancer.
A 2008 meta-analysis of 45 observational studies found no association between intake of vitamin D and prostate cancer risk. A meta-analysis published in 2011 reviewed 25 studies examining the link between prostate cancer incidence and indicators of vitamin D. Analysis of those studies found no association between dietary vitamin D or circulating concentrations of vitamin D and risk of prostate cancer.
Calcitriol, the hormonally active form of vitamin D, has been the focus of some studies in prostate cancer patients. In an open-label, phase II study, patients with recurrent prostate cancer were treated with calcitriol and naproxen for 1 year. The combination of calcitriol and naproxen was effective in decreasing the rate of rising PSA levels in study participants, suggesting it may slow disease progression. In a 2010 study, patients with castration-resistant prostate cancer were treated with calcitriol and dexamethasone. The results indicated that while the treatments were well tolerated, they did not have an effect on participants' PSA levels.
In a 2009 study, patients with locally advanced or metastatic prostate cancer and asymptomatic progression of their PSA levels were treated with vitamin D2 (ergocalciferol) at either 10 μg or 25 μg daily. The investigators reported that about 20% of these patients had at least a 25% drop in PSA level 3 months after initiating the vitamin D2.
Vitamin D toxicity
In most cases, symptoms of vitamin D toxicity are caused by hypercalcemia, but limited evidence suggests high concentrations of vitamin D may also be expressed in various organs, including the kidneys, bones, central nervous system, and cardiovascular system. Symptoms of toxicity may be observed at an intake of 10,000 to 50,000 IU per day over a period of many years. Hypercalcemia results from the vitamin D-dependent increase in intestinal absorption of calcium, leading to rapid increases in blood calcium levels. Side effects include loss of the urinary concentrating mechanism of the kidney tubule (resulting in polyuria and polydipsia), decrease in growth factor receptor, hypercalciuria, and the metastatic calcification of soft tissues. The central nervous system may also be affected, resulting in severe depression and anorexia.
A systematic review of the interactions and pharmacokinetics of vitamin D and drugs used for the treatment of cancer was published. Based on the review, 26 articles met the inclusion criteria. Calcitriol was the most commonly administered form of vitamin D, and adults with prostate cancer and solid tumors were the most well-represented populations in this systematic review. Hypercalcemia (at a dose of 74 μg/wk [3,000 IU]; 125 μg/wk [5,000 IU] with the addition of dexamethasone) was the most frequently reported side effect. Hypophosphatemia was also observed in two studies [37,38] that administered vitamin D in conjunction with docetaxel in men with prostate cancer. The authors concluded that no adverse effects were experienced beyond what was expected from high-dose calcitriol supplementation and was denoted as having a low risk of interaction. Some chemotherapeutic regimens appear to reduce serum 25(OH)-D3 and/or 1,25-D3.
A number of studies evaluated the safety and efficacy of high-dose calcitriol in conjunction with chemotherapy drugs in men with androgen-independent prostate cancer, hormone-refractory prostate cancer, and metastatic castration-resistant prostate cancer.[38,39,40] In the studies utilizing docetaxel plus calcitriol for men with androgen-independent prostate cancer, no increased toxicity was observed when compared with docetaxel alone.
In men with hormone-refractory prostate cancer, one study examined the activity and tolerability of weekly high-dose calcitriol (32 μg/wk [1,300 IU]) with docetaxel in patients who had previously received docetaxel treatment. Calcitriol was given orally in three divided doses, and docetaxel was given intravenously (30 mg /m2) with dexamethasone (8 mg) orally 12 hours before, at the time of, and 12 hours after docetaxel administration. Most of the side effects were expected toxicities related to the chemotherapy. Grade 2 hypercalcemia was observed in one patient. Administration of calcitriol was discontinued until hypercalcemia resolved. Supplementation was restarted after two weeks. In another patient, persistent grade 3 fatigue was observed, and treatment of calcitriol was discontinued as docetaxel was reduced.
Phase I trials
Phase I studies have looked at the maximum tolerated dose (MTD) of weekly intravenous and oral calcitriol in conjunction with various chemotherapy drugs for cancer treatment. One study examined the MTD of calcitriol in conjunction with gefitinib at 250 mg/day (oral chemotherapy used to treat lung cancer) in 32 patients with advanced solid tumors that were metastatic or unresectable. At doses up to 74 μg (3,000 IU) per week, no dose-limiting toxicities were observed. Grade 2 hypercalcemia was observed in two of four patients receiving 96 μg per week (3,900 IU) of calcitriol and was denoted nontolerable. No significant bone marrow suppression was observed at any dose. A dose of 74 μg (3,000 IU) per week was denoted as the MTD. The study suggests no major interaction between calcitriol and gefitinib.
A second phase I study examined the MTD and pharmacokinetics of calcitriol when administered with paclitaxel over the course of 6 weeks. Thirty-six patients (heterogenous diagnoses) were enrolled in the trial and received escalating doses of oral calcitriol starting at 4 μg (160 IU) for 3 consecutive days, and increasing to 38 μg (1,520 IU) with an 80-mg/m2 infusion of paclitaxel given weekly. Results demonstrate that very high doses of calcitriol can be safely administered with paclitaxel. There was no dose-limiting toxicity in the trial, and at a dose of 38 μg/wk, no clinically significant hypercalcemia occurred. However, it is important to note that participants were administered from 8 to 76 capsules of calcitriol with no report of adherence to the prescribed dose of calcitriol.
Vitamin E was discovered in 1922 as a factor essential for reproduction.
Vitamin E occurs in eight different forms: four tocopherols (alpha-, beta-, gamma-, and sigma-) and four tocotrienols (alpha-, beta-, gamma-, and sigma-). Compared with other tocopherols, alpha-tocopherol (the form of vitamin E commonly found in dietary supplements) is the most abundant in the body and the most biologically active. Most dietary vitamin E comes from gamma-tocopherol. Food sources of vitamin E include vegetable oil, nuts, and egg yolks.
The bioavailability of vitamin E depends on a number of factors, such as the food matrix containing vitamin E (e.g., low- or high-fat food). Vitamin E is delivered to tissues by high- and low-density lipoproteins (HDL and LDL, respectively). Delivery by LDL occurs via an endocytic pathway, while the protein's ATP -binding cassette, subfamily 1 and scavenger receptor class B type 1 (SR-BI) are involved in HDL vitamin E transport.
Research suggests that vitamin E may protect against a number of chronic diseases, such as cardiovascular disease. Many of vitamin E's health benefits have been ascribed to its actions as a powerful antioxidant; as with other antioxidants, vitamin E protects cell membranes by interfering with reactions that would form lipid hydroperoxide products. Vitamin E also has nonantioxidant functions: it has been shown to modulate signaling pathways and gene expression.
The National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study was initiated to examine whether supplemental vitamin E and dietary tocopherol intakes may prevent prostate cancer. Participants in the study completed food-frequency questionnaires and were monitored for 5 years. No association between vitamin E supplements and prostate cancer risk was found. However, a reduction in the risk of advanced prostate cancer was observed with high intakes of gamma-tocopherol.
In a 2010 study, levels of trace elements and vitamin E were measured in prostate cancer patients. Prostate cancer patients had significantly lower levels of plasma vitamin E than did healthy controls. In addition, there was an inverse association between prostate-specific antigen levels and plasma vitamin E.
Studies suggest that alpha-tocopherol-associated protein (TAP) may have capabilities as a tumor suppressor in prostate cancer. In a 2007 study, prostate cancer specimens, which had been obtained from radical prostatectomy, were examined for TAP expression. Results showed reduced TAP expression in prostate cancer tissue and lower levels of TAP were associated with higher clinical stage and larger tumor size.
A study published in 2011 examined serum alpha-tocopherol and supplemental vitamin E intake with sex steroid hormones in participants in the Third National Health and Nutrition Examination Survey (NHANES III). Results showed an inverse association between serum alpha-tocopherol levels and sex steroid hormones, but only in smokers.
Serum alpha-tocopherol and gamma-tocopherol levels and prostate cancer risk were examined in participants in the Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial. An inverse relationship was observed between alpha-tocopherol levels and prostate cancer, but only in current and recently former smokers. A meta-analysis of nine nested case-control studies, representing approximately 370,000 men from several countries, also found an inverse relationship between blood alpha-tocopherol levels and prostate cancer risk, but in all patients studied rather than limited to a smoking subset. No association was seen with gamma-tocopherol levels in this analysis. The risk of prostate cancer decreased by 21% for every 25 mg/L increase in blood alpha-tocopherol levels.
The North Carolina-Louisiana Prostate Cancer Project investigated racial and geographic differences in prostate cancer aggressiveness. The effects of food intake of tocopherols, vitamin E supplementation, and adipose tissue biomarkers of tocopherol were studied. In 1,023 African American men and 1,079 white men studied with incident prostate cancer, inverse associations were observed between dietary sources of tocopherol and prostate cancer aggressiveness that were statistically significant in white men but not in African American men.
The Physicians' Health Study II investigated whether vitamin C or vitamin E prevents prostate cancer and other cancers in men. Participants in the study were randomly assigned to receive vitamin E (synthetic alpha-tocopherol, 400 IU qod) and/or vitamin C (synthetic ascorbic acid, 500 mg /d) supplements and were monitored for an average of 8 years. The overall rates of prostate cancer were very similar in the vitamin E supplement and placebo groups, suggesting that vitamin E may not prevent prostate cancer. Furthermore, vitamin E did not have an effect on total cancer or mortality in these participants.
Although not primarily designed for this purpose, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study has been a resource for researchers investigating prostate cancer and vitamin E. A long follow-up study of participants in the ATBC Study was conducted. Baseline serum alpha-tocopherol levels and dietary intake of vitamin E had been assessed and participants were monitored for up to 19 years. Findings revealed that while there was no association between dietary vitamin E levels and prostate cancer risk, higher serum alpha-tocopherol levels may be associated with a decreased risk for developing advanced prostate cancer. In a 2009 study, blood samples obtained from participants in the ATBC Study were analyzed and genotyped. Results showed that genetic variations in the TTPA and SEC14L2genes were associated with serum alpha-tocopherol but did not directly affect prostate cancer risk. However, results suggested that polymorphisms in SEC14L2 may influence the effect of alpha-tocopherol supplementation on prostate cancer risk. One study also focused on the ATBC Study and investigated whether serum alpha-tocopherol levels affected survival time in men diagnosed with prostate cancer. Serum alpha-tocopherol levels were assessed at baseline and 3 years later. Higher serum alpha-tocopherol levels, at both baseline and the 3-year point, were associated with improved prostate cancer survival.
A 2011 study examined links between serum alpha- and gamma-tocopherols and risk of prostate cancer among participants in the Carotene and Retinol Efficacy Trial (CARET). CARET was a randomized, placebo-controlled study that investigated whether daily supplementation of beta-carotene and retinyl palmitate would reduce the risk of lung cancer in heavy smokers and asbestos -exposed workers. Results indicated that among current smokers, higher levels of serum alpha- and gamma-tocopherols were associated with reduced risk of aggressive prostate cancer. In addition, findings suggested there may be an interaction between myeloperoxidase (MGO) G-463A genotype, serum alpha-tocopherol level, and prostate cancer risk. Specific genotypes were associated with increased prostate cancer risk in subjects with low levels of serum alpha-tocopherol, while those same genotypes along with higher levels of alpha-tocopherol were associated with reduced risk of prostate cancer.
On the basis of findings from earlier studies,[14,19] the SELECT, a large multicenter clinical trial, was initiated by the NIH in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer. SELECT was a phase III, randomized, double-blind, placebo-controlled, population-based trial. More than 35,000 men, aged 50 years or older, from more than 400 study sites in the United States, Canada, and Puerto Rico were randomly assigned to receive vitamin E (all-rac-alpha-tocopherol acetate, 400 IU/d) and a placebo, selenium (L-selenomethionine, 200 µg/d) and a placebo, vitamin E and selenium, or two placebos daily for 7 to 12 years. The primary endpoint of the clinical trial was incidence of prostate cancer.
Initial results of SELECT were published in 2009. There were no statistically significant differences in rates of prostate cancer in the four groups. In the vitamin E-alone group, there was a nonsignificant increase in rates of prostate cancer (P = .06); in the selenium-alone group, there was a nonsignificant increase in incidence of diabetes mellitus (P = .16). On the basis of those findings, the data and safety monitoring committee recommended that participants stop taking the study supplements.
Updated results were published in 2011. When compared with placebo, the rate of prostate cancer detection was significantly greater in the vitamin E-alone group (P = .008) and represented a 17% increase in prostate cancer risk. There was also greater incidence of prostate cancer in men who had taken selenium than in men who had taken placebo, but those differences were not statistically significant.
Toenail selenium levels were assayed in a two-case cohort study of a subset of SELECT participants. Vitamin E supplementation (alone) had no effect among men with high selenium status at baseline but increased the risks of total (63%; P = .02), low-grade (46%; P = .09), and high-grade (111%; P = .008) prostate cancer among men with lower baseline selenium status. The authors concluded that men older than 55 years should avoid supplementation with either vitamin E or selenium at doses exceeding dietary recommendations. In a case-cohort analysis of 1,434 men in the SELECT who underwent analysis of single nucleotide polymorphisms in 21 genes, investigators found support for the hypothesis that genetic variation in selenium and vitamin E metabolism/transport genes may influence the risk of overall- and high-grade prostate cancer and that selenium or vitamin E supplementation may modify an individual's response to those risks.
The dose and form of vitamin E used in SELECT may have contributed to the results. On the basis of the results of the ATBC Study, all-rac-alpha-tocopheryl acetate was the form of vitamin E used in SELECT. The dose used in SELECT (400 IU) was higher than that in the ATBC Study. SELECT researchers opted for the higher dose because it was found in vitamin supplements, there was evidence for benefits of higher doses (including reductions in Alzheimer's disease and age-related macular degeneration), and it was thought the higher dose would be more protective against prostate cancer than a lower dose. Following the results of SELECT, it has been posited that high levels of alpha-tocopherol may affect levels of gamma-tocopherol, another form of vitamin E that may have chemopreventive effects. Another important difference between the ATBC Study and SELECT that may explain the findings was the smoking status of study participants. Participants in the ATBC Study were smokers, while 7.5% of SELECT participants used tobacco products.
Alpha-tocopherols have been deemed Generally Recognized as Safe by the U.S. Food and Drug Administration.
In the Physicians' Health Study II, there were no significant adverse effects reported for gastrointestinal tract symptoms, fatigue, drowsiness, skin discoloration or rashes, or migraine. However, participants who took vitamin E (alpha-tocopherol, 400 IU qod) experienced a greater number of hemorrhagic strokes than did participants who took placebo. An increase in hemorrhagic strokes among participants in the vitamin E group (alpha-tocopherol, 50 mg/d) also was noted in the ATBC Study.
In the initial report of results from SELECT, there were no significant differences between incidences of less severe adverse effects (e.g., alopecia, dermatitis, and nausea) experienced by the groups that received vitamin E (rac-alpha-tocopheryl acetate, 400 IU/d) and those experienced by the other treatment groups. Follow-up analysis of SELECT participants revealed an increased risk of prostate cancer among men in the vitamin E-alone group.
Pomi-T (Pomegranate, Green Tea, Broccoli, and Turmeric)
In a placebo-controlled, double-blind, randomized study, 199 men with localized prostate cancer were randomly assigned to either a food supplement, Pomi-T, or placebo (2:1) for 6 months. Pomi-T contained 100 mg each of pomegranate whole fruit powder, broccoli powder, and turmeric powder; and 20 mg of green tea extract (equivalent to 100 mg of tea). The herbal ingredients in this supplement were raw, dry, powdered plant materials and one plant extract, none of which were chemically standardized. Chemical standardization is widely performed with herbal extracts, as a means of enhancing the reproducibility of studies with herbal dietary supplements via qualitative and quantitative chemical analysis. There were no significant differences in age or Gleason score between the groups. Forty percent of the patients had rising prostate-specific antigen (PSA) levels following local therapy and 60% were on active surveillance (prelocal therapy). The study found a median rise in PSA of 14.7% after 6 months in the Pomi-T group compared with a 78.5% median rise in PSA in the placebo group. The supplement was well tolerated with no significant increase in adverse events compared with placebo, although a trend was noted towards increased flatulence and loose bowels in the supplement group.
Important differences exist between pomegranate preparation and standardization. While dried fruit powder is commonly found in the marketplace, an equal amount of pomegranate fruit extract has a much higher content of polyphenols that are considered the bioactive constituents and can be used for the chemical standardization of preparations.
Lycopene, Selenium, and Green Tea
In a randomized, double-blinded, placebo-controlled study of a supplement containing lycopene (35 mg), selenium (55 µg), and green tea catechins (600 mg) that was given for 6 months and targeted men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation, a higher incidence of prostate cancer was seen on rebiopsy in men who received the supplement. Although the expected (or historical) rate of progression to prostate cancer is less than 20% (even at 1 year), more than 25.5% of this population of men had a diagnosis of prostate cancer at 6 months, which may be attributed to inadequate sampling and potentially missed cancers at baseline. A high percentage of positive biopsies raises the concern for cancers missed on baseline biopsy, and thus, further study is warranted.
Lycopene and Other Components
One study randomly assigned 79 men before prostatectomy to a nutritional intervention with tomato products containing 30 mg of lycopene daily; tomato products plus selenium, omega-3 fatty acids, soy isoflavones, grape/pomegranate juice, and green/black tea; or a control diet for 3 weeks. There were no differences in PSA values between the intervention and control groups. However, a post hoc exploratory analysis found lower PSA values in men with intermediate-risk prostate cancer who consumed the tomato products and in men with the highest increases in lycopene levels.
General information and history
Zyflamend is a dietary supplement that contains supercritical fluid (CO2) and hydroalcoholic extracts of the following herbs, combined and suspended in olive oil:
The individual components of Zyflamend have anti-inflammatory and possible anticarcinogenic properties. For example, results of a 2011 study suggest that Zyflamend may inhibit the growth of melanoma cells.
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.
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.
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 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 antiapoptotic protein expression compared with cells treated with Zyflamend or bicalutamide alone.
Although the individual components of Zyflamend have been shown to influence COX activity, one study examined the effects of the drug on COX-1 and COX-2 expression in prostate cancer cells. The results revealed that Zyflamend, at a concentration of 0.9 μL/mL, inhibited expression of both COX-1 and COX-2. At a concentration of 0.45 μL/mL, the degree of COX-2 inhibition was observed, but the level of COX-1 inhibition was reduced by 50%. At a concentration of 0.1 μL/mL, Zyflamend effectively inhibited growth of prostate cancer cells and increased the level of caspase-3, a proapoptotic 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.
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 μL/mL to 2 μL/mL of 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.
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. A 2014 investigation by this team found that Zyflamend inhibits the expression of class I and class II histone deacetylases (HDAC) and upregulated their downstream target p21 suppressor gene. The extracts of the individual components of the 10 botanicals in Zyflamend were also evaluated in an effort to identify which compounds contributed most to the inhibition of HDAC expression. Chinese goldthread and baikal skullcap appeared to be the most likely major contributors to the overall Zyflamend effect on HDAC expression.
Additional evidence that Zyflamend promotes apoptosis in cancer cells was obtained in laboratory and animal studies reported in 2012. Treatment of human colorectal carcinoma cell lines in vitro with Zyflamend was shown to significantly down regulate expression of antiapoptotic proteins, up regulate expression of Bax (a proapoptotic 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 antiapoptotic proteins and significantly increased expression of DR5, compared with 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.
In one case report, a patient with 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.
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.
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.
Many widely available dietary supplements are marketed to support prostate health. African cherry (Pygeum africanum) and beta-sitosterol are two related supplements that have been studied as potential prostate cancer treatments. Note: A separate PDQ summary on PC-SPES is also available.
African Cherry/P. africanum
P. africanum is a tree from the Rosaceae family that grows in tropical zones. It is found in a number of African countries including Kenya, Madagascar, Uganda, and Nigeria. Bark from the P. africanum tree was used by African tribes to treat urinary symptoms and gastric pain. In the 18th century, European travelers learned from South African tribes that P. africanum was used to treat bladder discomfort and old man's disease (enlarged prostate).
Since 1969, bark extracts from P. africanum have been available as prescription drugs in Europe and have been widely used to treat benign prostatic hyperplasia.[2,3] The bark contains a number of compounds including saturated and unsaturated fatty acids, phytosterols (e.g., beta-sitosterol), pentacyclic triterpenoids (e.g., oleanolic acid), alcohols, and carbohydrates. The extract is obtained by macerating and solubilizing the bark in an organic solvent. The extract is then purified from the solvent.
Two components of P. africanum bark extracts, atraric acid and N-butylbenzene-sulfonamide, are androgen receptor inhibitors, as indicated by both in vitro[4,5,6] and animal in vivo studies. This activity is produced by each of these components at concentrations that are significantly lower than the clinically achieved concentration of the antiandrogen flutamide.
Beta-sitosterol is a member of the phytosterol family of phytochemicals. It is found ubiquitously in plants and has recently been classified as an invalid/improbable metabolic panacea (IMP) compound. Pygeum africanum, saw palmetto (Serenoa repens), and some legumes can contain rather high concentrations. As a type of phytosterol (or plant sterol), beta-sitosterol has a similar structure to cholesterol. Phytosterols, including beta-sitosterol, reduce absorption of dietary cholesterol and their potential to protect against cardiovascular disease is under investigation. Mean plasma beta-sitosterol concentration in a small group of healthy male volunteers in Vienna, Austria, was 2.83 μg /mL (approximately 7 μM). Interestingly, however, a rare condition caused by mutations in the adenosine triphosphate -binding cassette (ABC) transporter ABCG5 or ABCG8genes results in an inherited sterol storage disease with markedly increased serum concentrations of plant sterols such as sitosterol and leads to premature atherosclerosis and large xanthomas.
Research has also suggested that phytosterols may have anticarcinogenic properties, but the exact mechanisms are unknown. Phytosterols may exert antitumor effects by acting on immune and hormonal systems, or by directly targeting cell cycles and inducing apoptosis in tumor cells.
Beta-sitosterol at very high concentrations (i.e., 16 mM or 6.64 mg /mL) has been shown to significantly inhibit growth of PC-3 prostate cancer cells and induce apoptosis.[14,15] Beta-sitosterol is very poorly bioavailable, with an estimated 0.41% of dietary beta-sitosterol absorbed, and circulating blood levels of about 3 μg/mL to 9 μg/mL in individuals consuming diets containing normal to high amounts of plant-based foods (approximately 1,000 times less than the concentration used in the study).[10,16] Associated with these effects are decreasing levels of cell cycle regulators p21 and p27 in the cancer cells and an increased production of reactive oxygen species.
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of nutrition and dietary supplements for reducing the risk of developing prostate cancer or for treating 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.
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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Prostate Cancer, Nutrition, and Dietary Supplements. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/prostate-supplements-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389500]
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Last Revised: 2018-02-01
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