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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 summary on PC-SPES is also available.
Prostate cancer is the most common noncutaneous cancer affecting men in the United States. On the basis of data from 2017 to 2019, it is estimated that 12.6% of U.S. men will be diagnosed with prostate cancer during their lifetimes.[
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).[
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 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 health care professional.[
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.[
Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the
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.
For more information, see Prostate Cancer Prevention.
References:
Overview
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.[
The major sources of calcium in the U.S. population are food and dietary supplements.[
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 the 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), few studies include supplement use in the association of disease risk, including prostate cancer or mortality rates.[
Companies distribute calcium as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of calcium as a treatment for cancer.
Preclinical/Animal Studies
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.[
Human Studies
Epidemiological studies
Several epidemiological studies have found an association between high intakes of calcium, dairy foods, or both, and an increased risk of developing prostate cancer.[
Interventional studies
In a randomized clinical trial published in 2005, 672 men received either 3 g of calcium carbonate (1,200 mg calcium) or placebo daily for 4 years and were followed for 12 years. During the first 6 years of the study, there were significantly fewer prostate cancer cases in the calcium group compared with the placebo group. However, this difference was no longer statistically significant at the 10-year evaluation.[
Meta-analyses
A meta-analysis published in 2005 reported that there may be an association between increased risk of prostate cancer and greater consumption of dairy products and calcium.[
A 2008 meta-analysis reviewed 45 observational studies and found no evidence of a link between dairy products 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 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.[
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References:
Overview
This section contains the following key information:
General Information and History
Sailors first brought tea to England in 1644, although tea has been popular in Asia since ancient times. After water, tea is the most-consumed beverage in the world.[
In this 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,[
Several companies distribute green tea as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of green tea as a treatment for cancer or any other medical condition.
Preclinical/Animal Studies
In vitro studies
Prostate cancer cells treated with EGCG (concentrations, 0–80 μM) demonstrated suppressed cell proliferation and decreased levels of PSA protein and mRNA in the presence or absence of androgen.[
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.[
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.[
Animal studies
Animal models have been used in several studies investigating the effects of green tea on prostate cancer. In one study, TRAMP mice were given access to water or GTC–treated water (0.3% GTC solution; this exposure mimics human consumption of 6 cups of green tea daily). After 24 weeks, water-fed TRAMP mice had developed prostate cancer, whereas mice treated with GTCs showed only prostatic intraepithelial neoplasia lesions, suggesting that GTCs may help delay the development of prostate tumors.[
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).[
Using the TRAMP mouse model,[
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.[
In a study [
Human Studies
Epidemiological studies
The relationship between green tea intake and prostate cancer has been examined in several epidemiological studies.
Two meta-analyses examined the consumption of green tea and prostate cancer risk, with one meta-analysis including black tea.[
In Asian countries with a high per capita consumption of green tea, prostate cancer mortality rates are among the lowest in the world,[
Interventional studies
Bioavailability
Phase I/II intervention studies 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.[
Catechin tissue levels have also been reported, and high variations were quite common. Notably, catechin levels in prostate tissue were low to undetectable after the administration of Polyphenon E in one preprostatectomy study.[
| Source | EGCG Dose | Condition | Duration | Median Plasma EGCG Concentration (ng/mL) |
|---|---|---|---|---|
| EGCG = (−)-Epigallocatechin-3-gallate; kg = kilogram(s); mg = milligram(s); mL = milliliter(s); ng = nanogram(s); SD = standard deviation; wk = week(s); y = year. | ||||
| [ |
400 mg | Fed, fasted | 4 wk | 155.4 (fed), 161.4 (fasted) |
| 800 mg | Fed, fasted | 4 wk | 287.6 (fed), 390.36 (fasted) | |
| [ |
800 mg (in Polyphenon E) | Fed | 3–6 wk | 68.8 |
| [ |
2 mg/kg | Fasted | Single dose | 77.9 |
| [ |
200 mg (twice a day) | Fed | 1 y | 12.3 (SD, 24.8) |
Prevention
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.[
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).[
Preoperative studies
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 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.[
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Adverse Effects
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.[
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.[
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.[
Data from clinical trials [
In a 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.[
The FDA's Division of Drug Oncology Products has recommended that Polyphenon E be taken with food by subjects participating in clinical studies. In addition, frequent liver function tests should be considered while individuals are on treatment, especially in the first few months of trial initiation.
References:
Overview
This section contains the following key information:
General Information and History
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,[
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,[
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.[
The few human intervention trials have been small and generally focused on intermediate endpoints, not response of clinically evident disease or overall survival and, thus have limited translation to practice.[
On the basis of overall evidence, the association between tomato consumption and reduced risk of prostate cancer is limited.[
Several companies distribute lycopene as a dietary supplement. In the United States, dietary supplements are regulated by the FDA as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of lycopene as a treatment for cancer or any other medical condition.
Preclinical/Animal Studies
In vitro studies
In vitro studies that have examined a link between lycopene and prostate carcinogenesis have suggested several mechanisms by which lycopene might reduce prostate cancer risk. Lycopene is broken down into a number of metabolites that are thought to have various biological effects, including antioxidant capabilities and a role in gap-junction communication.[
Treating normal human prostate epithelial cells with lycopene resulted in dose-dependent growth inhibition, indicating that inhibition of prostate cell proliferation may be one way lycopene might lower the risk of prostate cancer.[
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.[
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.[
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.[
Animal studies
In a chemoprevention study, 59 transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed diets supplemented with tomato paste or lycopene beadlets (both preparations contained 28 mg lycopene/kg chow). Mice that received lycopene beadlets exhibited a larger reduction in prostate cancer incidence compared with control mice than mice supplemented with tomato paste, suggesting that lycopene beadlets may provide greater chemopreventive effects than tomato paste.[
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.[
Human Studies
Epidemiological studies
Several epidemiological studies have assessed potential associations between lycopene intake and prostate cancer incidence.
Epidemiological studies have demonstrated that populations with high intake of dietary lycopene have lower risk of prostate cancer.[
An association between lycopene serum concentration and risk of cancer was also examined in men participating in the Kuopio Ischaemic Heart Disease Risk Factor study in Finland. In this prospective cohort study, an inverse association between lycopene levels and overall cancer risk was observed, suggesting that higher concentrations of lycopene may help lower cancer risk overall. Men with the highest levels of serum lycopene had a 45% lower risk of cancer than did men with the lowest levels of lycopene (risk ratio [RR], 0.55; 95% confidence interval [CI], 0.34–0.89; P = .015). However, when the analysis was restricted to specific cancer types, an association was observed for other cancers (RR, 0.43; 95% CI, 0.23–0.79; P = .007) but not prostate cancer.[
A 2015 systematic review and meta-analysis of studies investigating dietary lycopene intake/circulating lycopene levels and prostate cancer risk found that when lycopene intake was higher, the incidence of prostate cancer was reduced (P = .078).[
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.[
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 American men, and diets high in beta-cryptoxanthin may protect against aggressive prostate cancer in African American men.[
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.[
In a recently reported prospective study of 27,934 U.S. Adventist men who were followed for up to 7.9 years, consumption of canned and cooked tomato-based products (measured as grams for both tomato products and lycopene), was inversely related to the risk of prostate cancer compared with those with zero intake of these foods. Associations of prostate cancer risk with raw tomatoes was not statistically significant. No differences in adjusted competing risk analyses were observed between aggressive and nonaggressive prostate cancers. The study was limited to self-reported food frequency questionnaires for data collection; however, lycopene concentrations were not quantified in this population.[
The variability in these epidemiological study results may be related to lycopene source; exposure misclassification; inconsistent measures of intake; differences in absorption; differences in individual lycopene metabolism; lack of a dose response; and confounding lifestyle factors, such as obesity, use of tobacco and alcohol, other dietary differences, varying standardization of quantities and compositions of lycopene, geographical location, and genetic risk factors. Most studies have examined the association of lycopene intake with the risk of all prostate cancers and have not separately considered indolent versus aggressive disease. Given these caveats, results based on epidemiological evidence should be interpreted with caution.
Interventional studies
A number of clinical studies have been conducted investigating lycopene as a chemopreventive agent and as a potential treatment for prostate cancer.
Bioavailability
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.[
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.[
Pharmacodynamic studies
Healthy men 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, and 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.[
Prevention/early treatment
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, 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).[
Treatment
A number of clinical trials investigating lycopene as a potential treatment for prostate cancer are listed below in Table 2.
| Reference | Trial Design | Agent/Dose/Duration | Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control) | Biomarkers | Results | Levels of Evidence b |
|---|---|---|---|---|---|---|
| Bid = twice a day; PSA = prostate-specific antigen; RCT = randomized controlled trial. | ||||||
| a For more information and definition of terms, see the |
||||||
| b Strongest evidence reported that the treatment under study has activity or improves the well-being of cancer patients. For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies. | ||||||
| [ |
Preprostatectomy; pilot RCT | Tomato oleoresin extract containing lycopene 30 mg/d (15 mg bid) or placebo control for 3 wk | 26; 15; 11 | Tumor volume | 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 high-grade prostatic intraepithelial neoplasia (33% vs. 0%, focal involvement) | 1iiDiii |
| [ |
Preprostatectomy; RCT | Tomato products containing 30 mg of lycopene daily, tomato products plusselenium,omega-3 fatty acids,soy isoflavones, grape/pomegranatejuice and green/black tea, or a control diet for 3 wk | 79; 27 (tomato), 25 (tomato plus); 27 (control) | PSA | No differences in PSA values between the intervention and control groups. Lower PSA values in men with intermediate-risk prostate cancer with highest increases in lycopene levels | 1Dii |
| [ |
Preprostatectomy; RCT | 15 mg, 30 mg, or 45 mg lycopene vs. control for 30 d | 45; 10 (15 mg), 10 (30 mg), 14 (45 mg); 11 (control) | PSA, steroid hormones, Ki-67 | 30 mg lycopene dose level decrease in free testosterone, significant increases in mean plasma estradiol and in serum sex hormone-binding globulin, and decrease in the percentage of cells expressing Ki-67; at the 45 mg/d dose, serum total estradiol increased | 1iiDii |
| [ |
Active surveillance; single arm | Whole-tomato supplement containing 10 mg of lycopene (Lycoplus) for 1 y | 40; 40; None | PSA velocity; PSA doubling time | Statistically significant decrease in PSA velocity after lycopene treatment (P = .0007) | 2Dii |
| [ |
Biochemical relapse after radiation therapy or surgery | 15, 30, 45, 60, 90, or 120 mg/d of lycopene (Lyc-O-Mato) for 1 y | 36; 36; None | PSA | Did not alter serum PSA levels | 2Dii |
| [ |
Biochemical relapse after radiation therapy or surgery; single-arm study | Tomato juice or paste containing lycopene 30 mg/d for 4 mo | 46; 46; None | PSA | Did not alter serum PSA levels except in one patient | 2Dii |
| [ |
Metastatic, hormone-refractory prostate cancer; open label study | Lycopene 10 mg/d (Lycored softules) for 3 mo | 20; 20; None | PSA | 50% had PSA levels that remained stable, 15% showed biochemical progression, 30% showed a partial response, and one patient exhibited a complete response after treatment | 2Dii |
| [ |
Hormone-refractory prostate cancer; single arm study | Lycopene 15 mg/d (pills) for 6 mo | 17; 17; None | PSA | PSA stabilization in 5 (29%) of 17 and PSA progression in 12 (71%) of 17 | 2Dii |
Preprostatectomy
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.[
In a phase II, randomized, placebo-controlled trial,[
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 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).
Current Clinical Trials
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Adverse Effects
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.[
The FDA has accepted the determination by various companies that their lycopene-containing products meet the FDA's requirements for the designation of GRAS.[
References:
Overview
This section contains the following key information:
General Information and History
Pectin is a complex polysaccharide contained in the primary cell walls of terrestrial plants. The word pectin comes from the Greek word for congealed or curdled. Plant pectin is used in food processing as a gelling agent also in the formulation of oral and topical medicines as a stabilizer and nonbiodegradable matrix to support controlled drug delivery.[
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.[
Several companies distribute MCP as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of MCP as a treatment for cancer or any other medical condition.
Preclinical/Animal Studies
In vitro studies
In a 2007 study, pectins were investigated for their anticancer properties. Prostate cancer cells were treated with three different pectins; 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.[
Animal studies
Only a few studies have been reported on the effects of MCP in animals bearing implanted cancers and only one involving prostate cancer.[
Human Studies
Interventional studies
In a 2007 pilot study, patients with advanced solid tumors (various types of cancers, including prostate cancer) received MCP (5 g MCP powder dissolved in water) 3 times a day for at least 8 weeks. Following treatment, improvements were reported in some measures of quality of life, including physical functioning, global health status, fatigue, pain, and insomnia. In addition, 22.5% of participants had stable disease after 8 weeks of MCP treatment, and 12.3% of participants had disease stabilization lasting more than 24 weeks.[
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.[
Current Clinical Trials
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Adverse Effects
In one prospective pilot study, MCP was well tolerated by the majority of treated patients, with the most commonly reported side effects being pruritus, dyspepsia, and flatulence.[
References:
Overview
This section contains the following key information:
General Information and History
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.[
Research studies suggest that pomegranates have beneficial effects on a number of health conditions, including cardiovascular disease,[
Several companies distribute pomegranate as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of pomegranate as a treatment or prevention for cancer or any other medical condition.
Preclinical/Animal Studies
In vitro studies
Research studies in the laboratory have examined the effects of pomegranate on many prostate cancer cell lines and in rodent models of the disease.
Ellagitannins (the main polyphenols in pomegranate juice) are hydrolyzed to ellagic acid, and then to urolithin A (UA) derivatives. According to a tissue distribution experiment in wild-type mice, the prostate gland rapidly takes up high concentrations of UA after oral or intraperitoneal administration (0.3 mg/mouse/dose). Ellagic acid (EA) was detected in the prostate following intraperitoneal, but not oral, administration of pomegranate extract (0.8 mg/mouse/dose).[
Treating human prostate cancer cells with individual components of the pomegranate fruit has been shown to inhibit cell growth.[
Pomegranate extracts have also been shown to inhibit the proliferation of human prostate cancer cells in vitro.[
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. [
Animal studies
The effects of pomegranate on prostate cancer have been examined using a number of rodent models of the disease. In one study, athymic nude mice were injected with tumor-forming cells. Following inoculation, animals were randomly assigned to receive normal drinking water or PJ (0.1% or 0.2% POMx in drinking water, which resulted in an intake corresponding to 250 or 500 mL of PJ per day for an average adult human). Small, solid tumors appeared earlier in mice drinking normal water only than in mice drinking PJ (8 days vs. 11–14 days). Moreover, tumor growth rates were significantly reduced in mice drinking PJ compared with mice drinking normal water only. Animals drinking PJ also exhibited significant reductions in serum PSA levels compared with animals drinking normal water only.[
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.[
Human Studies
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 level after surgery or radiation therapy for presumed localized cancer.[
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) (n = 47) or 3 g of pomegranate extract powder (n = 45 )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 they 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.[
Current Clinical Trials
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Adverse Effects
In a study of prostate cancer patients reported in 2006, the PJ intervention was well tolerated and no serious adverse effects were observed.[
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.[
References:
Overview
This section contains the following key information:
General Information and History
Selenium is an essential trace mineral involved in a number of biological processes, including enzyme regulation, gene expression, and immune function. Selenium was discovered in 1818 and named after the Greek goddess of the moon, Selene.[
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.[
Selenium is a component of the enzyme glutathione peroxidase, an enzyme that functions as an antioxidant.[
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.[
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.[
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.[
Some companies distribute selenium as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of selenium as a treatment or prevention for cancer.
Preclinical/Animal Studies
In vitro studies
Different selenium-containing compounds have variable effects on prostate cancer cells as well as normal cells and tissues. Both naturally occurring and synthetic organic forms of selenium have been shown to decrease the growth and function of prostate cancer cells.[
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.[
Sodium selenite
In a 2010 study, prostate cancer cells treated with sodium selenite (a natural form of selenium) exhibited increased levels of p53 (a tumor suppressor). Findings also revealed that p53 may play a key role in selenium-induced apoptosis.[
In a second study, the hormone-sensitive 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 hormone-insensitive 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.[
Animal studies
A 2012 study investigated whether various forms of selenium (i.e., SeMet and selenium-enriched yeast [Se-yeast]) differentially affect biomarkers in the prostate. Elderly dogs received nutritionally adequate or supranutritional levels of selenium in the form of SeMet or Se-yeast. Both types of selenium supplementation increased selenium levels in toenails and prostate tissue to a similar degree. The different forms of selenium supplementation showed no significant differences in DNA damage, proliferation, or apoptosis in the prostate.[
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.[
The effects of MSeA and methylselenocysteine (MSeC) have also been explored in a transgenic model of in situ murine prostate cancer development, the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse.[
Human Studies
Epidemiological studies
The results of epidemiological studies suggest some complexity in the association between the blood levels of selenium and the risk of acquiring prostate cancer. As part of the 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.[
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 SEP15genes were found to be associated with 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.[
An analysis of 4,459 men in the Health Professionals Follow-Up Study who were initially diagnosed with prostate cancer found that selenium supplementation of 140 μg or more per day after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality. The authors recommended caution in the use of selenium supplements among men with prostate cancer. Risk of prostate cancer mortality rose at all levels of selenium consumption. Men who consumed 1 to 24 μg/day, 25 to 139 μg/day, and 140 μg/day or more of supplemental selenium had a 1.18-fold (95% CI, 0.73–1.91), 1.33-fold (95% CI, 0.77–2.30), and 2.60-fold (95% CI, 1.44–4.70) increased prostate cancer mortality risk compared with nonusers, respectively (Ptrend = .001). The authors reported no statistically significant association between selenium supplement use and biochemical recurrence, cardiovascular disease mortality, or overall mortality.[
In summary, these epidemiological studies present a conflicting picture. Some studies showed that higher selenium levels were associated with a decreased risk of prostate cancer; others showed a correlation between higher selenium levels and more aggressive prostate cancer. Genetic differences in the SEPP gene may explain the different responses to selenium.
Interventional studies
Interventional studies have examined the efficacy of selenium in preventing and treating prostate cancer.
Prevention
In one study, 60 healthy 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 had significantly increased activities 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).[
However, in 2013, results of a phase III randomized, placebo-controlled trial were reported. The trial investigated the effect of selenium supplementation on prostate cancer incidence in men at high risk for the disease. Participants (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). The participants were monitored every 6 months for up to 5 years. Compared with placebo, selenium supplementation had no effect on prostate cancer incidence or PSA velocity.[
A 2018 Cochrane review that examined the role of selenium in cancer prevention consolidated these studies in a meta-analysis and noted a risk ratio of 1.01 (95% CI, 0.90–1.14) when four prostate cancer studies were reviewed that involved 18,942 patients.[
The Selenium and Vitamin E Cancer Prevention Trial (SELECT)
On the basis of findings from earlier studies,[
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 of SELECT were published in 2011. When compared with the placebo group, the rate of prostate cancer detection was significantly higher in the vitamin E–alone group (P = .008) and represented a 17% increase in prostate cancer risk. The incidence of prostate cancer was also higher in men who took selenium than in men who took placebo, but the differences were not statistically significant.[
A number of explanations have been suggested, including the dose and form of vitamin E used in the trial and 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.[
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. Although selenium supplementation in SELECT had no effect on prostate cancer risk among men with low selenium status at baseline, it 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.[
Complicating this picture, an international collaboration compiled and reanalyzed data from 15 studies, including the SELECT trial, that investigated the association between blood and toenail selenium concentrations and prostate cancer risk.[
In a case-cohort analysis of the SELECT trial, 1,434 men 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; selenium or vitamin E supplementation may modify an individual's response to those risks.[
In summary, data from the SELECT trial did not provide evidence that selenium, when given to unselected populations, decreased the risk of prostate cancer. Subsequent analyses have shown that baseline selenium levels may influence the outcomes of selenium supplementation, though the evidence remains conflicting. Emerging evidence suggests that SNPs in genes related to both selenium and prostate cancer likely modify the effect of selenium supplementation. Further research is needed to better understand which patients may benefit from or be harmed by selenium supplementation.
To date, the most recent literature demonstrates that when administered to a non-selected population, selenium has no significant effect on either prostate cancer prevention or PSA levels.
Treatment
A study explored the potential role of selenium in prostate cancer patients on active surveillance. It examined 140 men who 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. The results showed no significant difference in PSA velocity across treatment groups. Concerningly, men who received high-dose selenium and had the highest baseline plasma selenium levels, had a higher PSA velocity than did men in the placebo group. There was no significant effect of selenium supplements on PSA velocity in men who had lower baseline levels of selenium.[
Another study examined the potential role selenium played in the adjuvant setting. 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 who received supplements reported improved quality of life and showed decreases in low-density lipoprotein cholesterol and total cholesterol.[
Current Clinical Trials
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Adverse Effects
Selenium supplementation was well tolerated in many clinical trials. In two published trials, there were no differences reported in adverse effects between placebo or treatment groups.[
References:
Overview
This section contains the following key information:
General Information and History
Soybean, a major food source and a medicinal substance, has been used in China for centuries. Soybean was used as one of the early food sources in China.[
Although records of soy use in China date back to the 11th century BCE, it was not until the 18th century that the soy 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.[
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.[
A link between isoflavones and prostate cancer was first observed in epidemiological studies that demonstrated a lower risk of prostate cancer in populations consuming considerable amounts of dietary soy.[
Several companies distribute soy as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of soy as a treatment for cancer or any other medical condition.
Preclinical/Animal Studies
In vitro studies
Individual isoflavones
A number of laboratory studies have examined ways in which soy components affect prostate cancer cells. In one study, human prostate cancer cells and normal prostate epithelial cells were treated with either an ethanol vehicle (carrier) or isoflavones. Treatment with genistein decreased COX-2 mRNA and protein levels in cancer cells and normal epithelial cells more than did treatment with the vehicle. In addition, cells treated with genistein exhibited reduced secretion of prostaglandin E2 (PGE2) and reduced mRNA levels of the prostaglandin receptors EP4 and FP, suggesting that genistein may exert chemopreventive effects by inhibiting the synthesis of prostaglandins, which promote inflammation.[
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, daidzein, 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.[
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 studies
Animal models of prostate cancer have been used in studies investigating the effects of soy and isoflavones on the disease. Wild-type and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control diets or diets containing genistein (250 mg genistein/kg chow). The TRAMP mice fed with genistein exhibited reduced cell proliferation in the prostate compared with TRAMP mice fed a control diet. The genistein-supplemented diet also reduced levels of ERK-1 and ERK-2 (proteins important in stimulating cell proliferation) as well as the growth factor receptors epidermal growth factor receptor (EGFR) and insulin like growth factor-1 receptor (IGF-1R) in TRAMP mice, suggesting that down regulation of these proteins may be one mechanism by which genistein exerts chemopreventive effects.[
In a study reported in 2008, athymic mice were implanted with human prostate cancer cells and fed a control or genistein-supplemented diet (100 or 250 mg genistein/kg chow). Mice that were fed genistein exhibited less cancer cell metastasis but no change in primary tumor volume, compared with mice fed a control diet. Furthermore, other data suggested that genistein inhibits metastasis by impairing cancer cell detachment.[
In contrast, in a study reported in 2011, there were more metastases in secondary organs in genistein-treated mice than in vehicle-treated mice. In this latter study, mice were implanted with human prostate cancer xenografts and treated daily with genistein dissolved in peanut oil (80 mg genistein/kg body weight/d or 400 mg genistein/kg body weight/d) or peanut oil vehicle by gavage. In addition, there was a reduction in tumor cell apoptosis in the genistein-treated mice compared with the vehicle-treated mice. These findings suggest that genistein may stimulate metastasis in an animal model of advanced prostate cancer.[
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.[
In the treatment of prostate cancer, bone health is a common concern in the setting of hormone deprivation therapy, which is associated with bone loss. Because of increased beta versus alpha estrogen receptor binding, soy-derived compounds are thought to be protective of bone. Animal studies have shown that genistein and daidzein can prevent or reduce bone loss in a manner similar to synthetic estrogen. Both isoflavones may modulate bone remodeling by targeting and regulating gene expression and may inhibit calcium urine excretion, which also helps to maintain bone density.[
Human Studies
Human studies evaluating isoflavones and soy for the prevention and treatment of prostate cancer have included epidemiological studies and early-phase trials. Several phase I-II randomized clinical studies have examined isoflavones and soy product for bioavailability, safety, and effectiveness in prostate cancer prevention or treatment.[
Epidemiological studies
In 2018, a meta-analysis of studies that investigated soy food consumption and risk of prostate cancer was reported. The results of this meta-analysis suggested that high consumption of nonfermented soy foods (e.g., tofu and soybean milk) was significantly associated with a decrease in the risk of prostate cancer. Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with a reduced risk of prostate cancer.[
Prevention studies
Too few randomized placebo-controlled trials have been completed to evaluate the effect of isoflavones or soy in preventing prostate cancer progression (see Table 3). The studies targeted men with negative prostate biopsies and elevated serum prostate-specific antigen (PSA) (2.5–10 mcg/mL at baseline). The duration of intervention was between 6 months [
| Reference | Isoflavone Dose | Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control) | Duration of Intervention | Toxicities | Results | Levels of Evidence b | |
|---|---|---|---|---|---|---|---|
| ALT = alaninetransaminase;AST =aspartate transaminase; PCa = prostate cancer; PSA = prostate-specific antigen. | |||||||
| a Men with a negative biopsy and elevated PSA max 10 mcg/mL. | |||||||
| b Strongest evidence reported that the treatment under study has activity or improves the well-being of cancer patients. For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies. | |||||||
| [ |
Soy isoflavones (40 mg/d; comprising 66% daidzein, 24% glycitin, and 10% genistin) and curcumin (100 mg/d) versus placebo | 85; 43; 42 | 6 mo | No significantadverse effectseither in the placebo or supplement groups; one subject on placebo experienced severediarrheaduring the trial and dropped out subsequently | Decrease in serum PSA (P< .05) | 1iDii | |
| [ |
60 mg/d isoflavone extract from red clover | 20; 20; None | 12 mo | Significant increase in ALT and AST after 3 mo (P< .001) | Decrease in serum PSA (P< .05) | 2Dii | |
| [ |
60 mg/d isoflavones | 158; 78; 80 | 12 mo | Two patients had grade 3 adverse events, one in the isoflavone group suffered iliacarterystenosis and the other in the placebo group sufferedileus; other adverse events were mild in severity | Decrease in PCa incidence in men older than 65 years with isoflavones (P< .05) | 1iDi | |
Treatment of prostate cancer
Clinical trials evaluating isoflavones, soy supplements, and soy products (see Table 4 and Table 5) for treating localized prostate cancer before radical prostatectomy have used window-of-opportunity trial designs (from biopsy to prostatectomy). These trials have primarily focused on evaluating serum and tissue biomarkers implicated in prostate cancer progression, bioavailability in plasma and prostate tissue, and toxicity at various doses. The trials are small in size and of short duration. They are useful for informing the design of well-powered larger clinical trials in the future, but they provide inadequate data to inform clinical practice.
Isoflavones
| Reference | Isoflavone Dose | Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control) | Duration of Intervention | Toxicities | Results | Levels of Evidencea | |
|---|---|---|---|---|---|---|---|
| AR = androgen receptor; PSA = prostate-specific antigen. | |||||||
| a Strongest evidence reported that the treatment under study has activity or improves the well-being of cancer patients. For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies. | |||||||
| [ |
30 mg/d genistein | 54; 23; 24 | 3–6 wk | Clinical adverse events were Grade 1 (mild); two biochemical adverse events recorded, both in the genistein group (one increase in serum lipase, one increase in serumbilirubin) potentially related tostudy agent | Decrease in serum PSA (P< .05), decrease in totalcholesterol(P< .01), increase in plasma genistein (P< .001) | 1iDiii | |
| [ |
Soy isoflavonecapsules(total isoflavones, 80 mg/d) | 86; 42; 44 | 6 wk | All adverse events were Grade 1 (mild) | Changes in serum total testosterone, free testosterone, total estrogen, estradiol, PSA, and total cholesterol in the isoflavone-treated group compared with men receiving placebo were notstatistically significant | 1iDii | |
| [ |
Supplement containing 450 mg genistein, 300 mg daidzein, and other isoflavones/d versus placebo followed by open-label | 53; 28; 25 | 6 mo intervention followed by 6 mo open label (active surveillance) | Not evaluated | Significant increase in serum genistein and daidzein; no significant findings regarding serum PSA changes | 1iDii | |
| [ |
Isoflavone tablets (60 mg/d) | 60; 25; 28 | 4–12 wk | Adverse events were Grade I and II in both groups, with two events that were identified as Grade III in the treatment arm and determined to be unrelated to agent (constitutional symptoms offeverrelated to aviral infection) | Increase in plasma isoflavones (P< .001) in the isoflavone-treated group versus placebo; greater concentrations of plasma isoflavones daidzein (P = .02) and genistein (P = .01) were inversely correlated with changes in serum PSA | 1iDii | |
| [ |
Isoflavone capsules 40, 60, or 80 mg | 45;12 (40 mg), 11 (60 mg) ,10 (80 mg); 11 | 27–33 d | Adverse events were Grade I-II | Increased plasma isoflavones at all doses; increased serum total estradiol in the 40 mg (P = .02) isoflavone-treated arm versus placebo; increased serum-free testosterone in the 60 mg isoflavone-treated arm (P = .003) | 1iiDii | |
| [ |
Cholecalciferol(vitaminD3) 200,000IU+ genistein (G-2535) 600 mg/d | 15; 7; 8 | 21–28 d | Adverse events occurred in four patients in the placebo group and five patients in the vitamin D + genistein group | Increased AR expression (P< .05); no other significant findings | 1iiDii | |
Soy protein or whole soy products
| Reference | Intervention Dose | Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control) | Duration of Intervention | Toxicities | Results | Levels of Evidencea | |
|---|---|---|---|---|---|---|---|
| COX = cyclooxygenase; GI = gastrointestinal; PSA = prostate-specific antigen. | |||||||
| a Strongest evidence reported that the treatment under study has activity or improves the well-being of cancer patients. For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies. | |||||||
| [ |
Soy supplement with 60 mg isoflavone versus placebo supplement | 60; 29; 30 | 12 wk | Nine grade I-II GI toxicities in the placebo group and eight from the isoflavone group | No significant findings | 1iDii | |
| [ |
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 | 19; 11; 8 | 2 wk beforesurgery | Not evaluated | Higher isoflavone concentration (x6) in tissue than in serum following treatment with the soy supplements | 1iDiii | |
| [ |
Soy isoflavone supplements (total isoflavones, 160 mg/d and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein) | 33; 17; 16 | 12 wk | Not evaluated | No significant difference between groups | 1iDii | |
| [ |
Soy (high phytoestrogen), soy andlinseed(high phytoestrogen), or wheat (low phytoestrogen) | 29; 8 (soy), 10 (soy and linseed); 8 (wheat) | 8–12 wk | Not evaluated | Reduction intotal PSA(P = .02); percentage of change in free/total PSA ratio (P = .01); percentage of change in free androgen index (P = .04) | 1iDii | |
| [ |
Soy isoflavone supplement (providing isoflavones, 81.6 mg/d) or placebo | 25; 13; 12 | 2 wk before surgery (pilot) | Not evaluated | Decrease in COX-2 mRNA levels (P< .01); increases in p21 mRNA levels (P< .01) in prostatectomy specimens obtained from the soy-supplemented group compared with placebo group | 1iDii | |
Isoflavones and soy products for biochemical recurrence after treatment
Other studies have examined the role of isoflavones and soy products in prostate cancer patients with biochemical recurrence after treatment. However, these early-phase studies have not demonstrated any significant changes in serum PSA or PSA-doubling time, [
| Reference | Trial Design | Dose | Duration of Intervention | Treatment Group (Enrolled; Treated; Placebo or No Treatment Control) | Toxicities | Results | Levels of Evidencea |
|---|---|---|---|---|---|---|---|
| GCP = genistein combined polysaccharide; GI = gastrointestinal; PCa = prostate cancer; RCT = randomized controlled trial. | |||||||
| a Strongest evidence reported that the treatment under study has activity or improves the well-being of cancer patients. For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies. | |||||||
| [ |
Nonrandomized | Soy beverage daily (providing approximately 65–90 mg isoflavones) | 6 mo | 34; 29; None | Adverse events included minor GI side effects | No statistically significant findings regarding PSA, PSA-doubling time | 2C |
| [ |
Open-label | Soy milk 3x/d (isoflavones, 141 mg/d) | 12 mo | 20; 20; None | Toxicity data lacks details; GI (loosestools) toxicities were the most common complaint from a small number of men in the GCP group | No statistically significant findings regarding serum PSA changes | 2Dii |
| [ |
RCT | Beverage powder containing soy-protein isolate (20 g protein) or calcium caseinate | 2 y | 177; 87; 90 | All adverse events were grades I-II; there were no differences in adverse events between the two groups | No significant findings regarding serum PSA changes | 1iDii |
| [ |
RCT | Two slices of soy bread containing 68 mg/d soy isoflavones or soy bread containing almond powder | 56 d | 32; 25; None | Soy and soy-almond breads were without grade 2 or higher toxicity | Significant modulation of multiple plasmacytokinesand chemokines | 1iiDii |
Management of androgen deprivation therapy side-effects
ADT is commonly used for locally advanced and metastatic prostate cancer. However, this treatment is associated with a number of adverse side effects including sexual dysfunction, decreased quality of life, changes in cognition, and metabolic syndrome. Three studies have examined men undergoing ADT who were randomly assigned to receive a placebo or an isoflavone supplement (soy protein powder mixed with beverages; isoflavones, 160 mg/d) for 12 weeks. Two studies assessed ADT side effects. Neither study found an improvement in side effects following isoflavone treatment, compared with placebo.[
The third randomized placebo-controlled trial assessed changes in PSA level and biomarkers of energy metabolism (e.g., blood glucose level) and inflammation (e.g., blood interleukin-6 level). In this study of men undergoing ADT, participants were randomly assigned to receive high-dose isoflavone supplements (providing 160 mg/d total isoflavones, and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein) or a placebo for 12 weeks. The results showed no difference between the two groups in PSA levels or in levels of metabolic and inflammatory parameters (e.g., glucose, interleukin-6).[
Current Clinical Trials
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Adverse Effects
Overall, isoflavones, soy, and soy products were well tolerated in clinical trials of high-risk prostate cancer patients.[
References:
Overview
General Information and History
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.[
Companies distribute vitamin D as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of vitamin D as a treatment for cancer.
Preclinical/Animal Studies
In vitro studies
To study the role of vitamin D in cancer cell adhesion to endothelium, one study developed a microtube system that simulates the microvasculature of bone marrow. The study reported that 1,25-alpha-dihydroxyvitamin D3 (1,25-D3) suppressed adhesion of prostate cancer cells in the microtube system. In addition, it was shown that 1,25-D3 increased E-cadherin expression, which may prevent prostate cancer cell adhesion to endothelium by promoting cancer cell aggregation.[
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 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.[
Androgen metabolism in prostate cancer cells may be altered by 1,25-dihydroxyvitamin D (1,25(OH)2 D), providing an additional antitumor mechanism. Vitamin D compounds activate enzymes involved in cholesterol and steroid hormone metabolism. This may reduce intracellular testosterone levels in prostate cell lines and decrease the availability of pro-survival androgenic steroids.[
Vitamin D has also been combined with radiation in an in vitro study. In this study, prostate cancer cells were treated with valproic acid (VPA) and/or 1,25-D3, followed by radiation. Cells that were treated with VPA and/or 1,25-D3 and radiation had greater decreases in cell proliferation than did cells treated solely with radiation. The greatest reduction in cell proliferation occurred in cells treated with VPA, 1,25-D3, and radiation.[
In vivo studies
Tumor progression was compared in two murine models of prostate cancer. In vitamin D receptor–knockout animals, the rate of tumor progression and cellular proliferation were greater than in wild type animals. However, in mice that were supplemented with testosterone, these differences did not occur, suggesting that there may be significant interaction between androgen signaling and vitamin D signaling.[
In a 2011 study, nude mice were fed a control diet or a diet deficient in vitamin D and then injected with prostate cancer cells into bone marrow or soft tissues. Osteolytic lesions were larger and progressed at a faster rate in vitamin D–deficient mice that had bone marrow injected with cancer cells than in mice that had adequate levels of vitamin D. However, there was no difference in soft tissue tumors among mice with different vitamin D levels. Results of this study show that vitamin D deficiency is associated with growth of prostate cancer cells in bone but not in soft tissue.[
A 2014 study evaluated calcitriol and a less-calcemic vitamin D analogue in an aggressive transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Neither vitamin D analogue impacted the rate of development of castration -resistant prostate cancer in mice, whether they were treated before or after castration. However, both vitamin D analogs slowed progression of primary tumors in hormone-intact mice but enhanced distant organ metastases after prolonged treatment. In sum, intervention with potent vitamin D compounds in TRAMP mice slowed androgen-stimulated tumor progression but, over time, may have led to more aggressive disease as indicated by increased distant metastases (P = .0823).[
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.[
In vitro and in vivo studies have shown that vitamin D compounds potentiate the cytotoxicity of many anticancer agents, including docetaxel.[
Human Studies
Epidemiological studies
The relationship between vitamin D and prostate cancer has been examined in numerous epidemiological studies with mixed results. A meta-analysis published in 2011 reviewed 25 studies that examined the link between prostate cancer incidence and indicators of vitamin D intake or sufficiency. No association was found between dietary vitamin D or circulating concentrations of vitamin D and risk of prostate cancer.[
Low sun exposure
An important means of obtaining vitamin D is by sunlight. Studies have investigated the potential link between sunlight exposure and prostate cancer. According to a 2006 study, prostate-specific antigen (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.[
Dietary vitamin D
The association between dietary vitamin D or circulating concentrations of vitamin D and risk of prostate cancer has been studied. In a study of 699 patients with prostate cancer who underwent screening and 958 healthy controls, calcium and vitamin D intake were evaluated using food frequency questionnaires.[
In a cross-sectional analysis of 119 men (88 African American patients and 31 European American patients) who underwent a prostatectomy, tumor proliferation (as indicated by Ki-67 measured in prostate tissue) demonstrated an inverse correlation between serum 1,25(OH)2 D and Ki-67 in tumor cells. These results provided preliminary evidence of an antiproliferative activity of vitamin D. No correlation was observed between 25(OH)D and a biomarker of tumor proliferation (Ki-67).[
Serum 25(OH)D
A meta-analysis of 19 prospective or cohort studies examined the correlation between circulating 25(OH)D and the development of prostate cancer. The study explored the summary relative risk (RR) assessed per 10 ng/mL increments in circulating 25(OH)D concentration levels.[
Another meta-analysis of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2 D for up to 13,462 men with incident prostate cancer and 20,261 control participants. Results showed that 25(OH)D concentration was positively associated with a risk of total prostate cancer (multivariable-adjusted OR that compared highest vs. lowest study-specific fifth, 1.22; 95% CI, 1.13–1.31; Ptrend < .001).[
In a case-control study of men who had undergone prostate biopsies, results showed that 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.[
Genetic factors
Investigators conducted an updated two-sample mendelian randomization analysis that examined the effect of 25(OH)D on prostate cancer.[
Several studies have explored a possible connection between the vitamin D receptor (VDR) and risk of prostate cancer. A 2011 prospective study (N = 841) examined VDR expression in prostate tumors. Patients with high levels of VDR expression had lower PSA levels 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 patients with prostate cancer who participated in the Prostate Testing for Cancer and Treatment (ProtecT) trial (N = 1,604). This analysis was combined with information from a meta-analysis of 13 studies. 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 (Bsm1, Apa1, and Taq1) may be associated with cancer grade (Gleason score). This suggests that there may be a link between specific VDR polymorphisms and advanced prostate cancer at diagnosis.[
In a retrospective study of 515 patients with prostate cancer and an independent cohort of 411 patients, two VDR binding site variants (HFE and TUSC3) were identified as plausible susceptibility genes.[
A meta-analysis of 27 studies was conducted that included 9,993 prostate cancer cases and 9,345 controls. The pooled results showed that the Bsm1 polymorphism of vitamin D metabolism was not associated with prostate cancer risk in an overall analysis.[
Survival
In a Danish Prostate Cancer Registry, a total of 4,065 men who underwent a prostate biopsy and had a vitamin D level checked between 2004 and 2010 were monitored.[
One analysis examined 943 participants who were diagnosed with prostate cancer and enrolled in the Malmö Diet and Cancer Study. The relationship between prediagnostic levels of vitamin D (25(OH)D) and survival was examined.[
One hundred ninety men who participated in a large epidemiological study underwent radical prostatectomy for clinically localized prostate cancer.[
In the MARTINI-Lifestyle cohort study, biochemical recurrence (BCR) after radical prostatectomy was studied in 3,849 men who were followed for 3 years and had levels of serum 25(OH)D concentrations measured at the time of surgery.[
In another retrospective study, 111 men with prostate cancer had serum levels of plasma 25(OH)D and 1,25(OH)2 D measured at 4.9 years or 8.6 years postdiagnosis. An analysis examined all-cause and prostate-specific mortality.[
A study of 943 patients with prostate cancer examined serum levels of vitamin D and aggressive prostate cancer.[
In a study of 155 African American men with prostate cancer, vitamin D levels were measured at diagnosis.[
Interventional studies
In a 2009 study, patients with locally advanced or metastatic prostate cancer and asymptomatic progression of their PSA levels were treated with vitamin D2 (ergocalciferol) at either 10 μg or 25 μg daily. The investigators reported that about 20% of these patients had at least a 25% drop in PSA level 3 months after initiating the vitamin D2.[
Calcitriol (1,25-dihydroxy vitamin D), the hormonally active form of vitamin D, has been the focus of some studies in prostate cancer patients. In an open-label, phase II study, patients with recurrent prostate cancer were treated with calcitriol and naproxen for 1 year. This treatment was effective in decreasing the rate of rising PSA levels in study participants, suggesting it may slow disease progression.[
In a 2018 randomized controlled trial, men aged 50 years or older and women aged 55 years or older received vitamin D3 (cholecalciferol) and omega-3 fatty acid supplements for the prevention of cancer and cardiovascular disease. The vitamin D supplement did not result in a lower incidence of any cancer, including prostate cancer, or cardiac disease compared with a placebo.[
A systematic review and meta-analysis of 16 before-after studies and 6 randomized controlled studies evaluated the effect of vitamin D supplementation on PSA change, PSA response proportion, mortality, and adverse effects. The analysis of controlled clinical trials found no significant difference between vitamin D supplementation and the placebo groups for PSA change from baseline (weighted mean difference, -1.66 ng/mL; 95% CI, -0.69 to 0.36; P = .543), PSA response proportion (RP) (RP, 1.18; 95% CI, 0.97–1.45; P = .104), and mortality rate (RR, 1.05; 95% CI, 0.81–1.36; P = .713). Single-arm trials revealed that vitamin D supplementation had a modest effect on PSA response proportion. Nineteen percent of enrolled patients had at least a 50% reduction in PSA levels by the end of treatment (95% CI, 7%–31%; P = .002). The authors believed that the evidence from these studies did not show important benefits from vitamin D supplementation and thus such supplementation should not be recommended as part of treatment.[
A post hoc analysis was conducted on data from two randomized controlled trials. Patients with castration-resistant prostate cancer received the combination of a statin and vitamin D with abiraterone (AA). The analysis reported that one study (COU-AA-301) found that the use of AA with a statin and vitamin D reduced the risk of death by 38% (P = .0007), while AA alone was associated with a decrease in the risk of death by 10% (P = .025). The second study (COU-AA-302) compared AA plus a statin and vitamin D with prednisone alone and found that the use of AA plus a statin and vitamin D was associated with a reduced risk of death by 26% (P = .0054).[
Symptom management
A small group of patients (N = 59) who underwent androgen deprivation therapy (ADT) were randomly assigned to receive high-dose vitamin D (600 IU /day plus 50,000 IU/week), low-dose vitamin D (600 IU/day), or a placebo for 24 weeks.[
| Reference | Trial Design | Dose | Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control) | Results | Levels of Evidence b |
|---|---|---|---|---|---|
| IV =intravenous; PSA = prostate-specific antigen; RCT = randomized controlled trial. | |||||
| a For more information and definition of terms, see the |
|||||
| b Strongest evidence reported that the treatment under study has activity or improves the well-being of cancer patients. For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies. | |||||
| [ |
Case series | Ergocalciferol, 10 μg or 25 μg, once daily | 26; 26; None | 20% of patients had at least a 25% drop in PSA level 3 months after initiating vitamin D2 | 3Diii |
| [ |
Open-label, phase II | Calcitriol, 45 μg 1/wk and naproxen, 375 mg, twice daily | 21; 20; None | Treatment was effective in decreasing the rate of rising PSA levels | 3Diii |
| [ |
Phase II | Calcitriol IV, 74 μg, once weekly andoraldexamethasone, 4 mg, twice weekly | 18; 18; None | No change in the PSA level | 3Diii |
| [ |
RCT | Cholecalciferol, 2000 IU daily and omega-3 fatty acid, 1 g daily | 25,871; 12,927 (active vitamin D); 12,944 (placebo vitamin D) | Vitamin D did not result in a lower incidence of any cancer, including prostate cancer, or cardiac disease | 1iiB |
| [ |
RCT | High-dose vitamin D (600 IU daily plus 50,000 IU weekly) or low-dose vitamin D (600 IU daily) | 59; 29 (high dose); 30 (low dose) | Muscle mass improved with high-dose vitamin D3 supplementation, but strength did not | 2C |
Adverse Effects
Vitamin D toxicity
In most cases, symptoms of vitamin D toxicity are caused by hypercalcemia, but limited evidence suggests high concentrations of vitamin D may also be expressed in various organs, including the following:
Symptoms of toxicity may be observed at an intake of 10,000 to 50,000 IU per day over a period of many years. Hypercalcemia results from the vitamin D–dependent increase in intestinal absorption of calcium, leading to rapid increases in blood calcium levels. Side effects include loss of the urinary concentrating mechanism of the kidney tubule (resulting in polyuria and polydipsia), decrease in growth factor receptor, hypercalciuria, and the metastatic calcification of soft tissues. The central nervous system may also be affected, resulting in severe depression and anorexia.[
A systematic review of the interactions and pharmacokinetics of vitamin D and drugs used for the treatment of cancer was published.[
Hypophosphatemia was also observed in two studies [
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.[
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.[
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.[
A second phase I study examined the MTD and pharmacokinetics of calcitriol when administered with paclitaxel over the course of 6 weeks.[
References:
Overview
General Information and History
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-).[
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).[
Research suggests that vitamin E may protect against a number of chronic diseases, such as cardiovascular disease.[
Companies distribute vitamin E as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of vitamin E as a treatment for cancer.
Human Studies
Epidemiological studies
The National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study was initiated to examine whether supplemental vitamin E and dietary tocopherol intakes may prevent prostate cancer. Participants in the study completed food-frequency questionnaires and were monitored for 5 years. No association between vitamin E supplements and prostate cancer risk was found. However, a reduction in the risk of advanced prostate cancer was observed with high intakes of gamma-tocopherol.[
In a 2010 study, levels of trace elements and vitamin E were measured in prostate cancer patients who had significantly lower levels of plasma vitamin E than did healthy controls. In addition, there was an inverse association between prostate-specific antigen levels and plasma vitamin E.[
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.[
The North Carolina-Louisiana Prostate Cancer Project investigated racial and geographic differences in prostate cancer aggressiveness.[
Interventional studies
The Physicians' Health Study II investigated whether vitamin C or vitamin E prevents prostate cancer and other cancers in men. Participants were randomly assigned to receive vitamin E (synthetic alpha-tocopherol, 400 IU qod) and/or vitamin C (synthetic ascorbic acid, 500 mg /d) supplements and were monitored for an average of 8 years. The overall rates of prostate cancer were very similar in the vitamin E supplement and placebo groups, suggesting that vitamin E may not prevent prostate cancer. Furthermore, vitamin E did not have an effect on total cancer or mortality in these participants.[
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 2011 study examined links between serum alpha- and gamma-tocopherols and risk of prostate cancer among participants in the Carotene and Retinol Efficacy Trial (CARET). CARET was a randomized, placebo-controlled study that investigated whether daily supplementation of beta-carotene and retinyl palmitate would reduce the risk of lung cancer in heavy smokers and asbestos -exposed workers. Results indicated that among current smokers, higher levels of serum alpha- and gamma-tocopherols were associated with reduced risk of aggressive prostate cancer. In addition, findings suggested there may be an interaction between myeloperoxidase (MGO) G-463A genotype, serum alpha-tocopherol level, and prostate cancer risk. There was an inverse relationship between prostate cancer risk and serum alpha-tocopherol levels in certain genotypes.[
The Selenium and Vitamin E Cancer Prevention Trial (SELECT)
On the basis of findings from earlier studies,[
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 in 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.[
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.[
Current Clinical Trials
Use our
Adverse Effects
Alpha-tocopherols have been deemed Generally Recognized as Safe by the FDA.[
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.[
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.[
References:
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.[
Important differences exist between the various pomegranate preparations and their 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 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.[
Zyflamend
Overview
General information and history
Zyflamend is a dietary supplement that contains CO2 and hydroalcoholic extracts of the following herbs, combined and suspended in olive oil:
The individual components of Zyflamend have anti-inflammatory and possible anticarcinogenic properties. For example, results of a 2011 study suggest that Zyflamend may inhibit the growth of melanoma cells.[
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.[
Several companies distribute Zyflamend as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of Zyflamend as a treatment for cancer or any other medical condition.
Preclinical/animal studies
In vitro studies
In a study reported in 2012, human prostate cancer cells were treated in vitro with Zyflamend. Cells treated with the supplement at concentrations ranging from 0.06 to 0.5 μL /mL exhibited dose-dependent decreases in androgen receptor and 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.[
Animal studies
Additional evidence that Zyflamend promotes apoptosis in cancer cells was obtained in laboratory and animal studies reported in 2012.[
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.[
Human studies
Interventional studies
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.[
Adverse effects
Zyflamend was well tolerated in the previously described 2009 clinical study. Mild heartburn was reported in 9 of 23 subjects, but it resolved when the study supplements were taken with food. No serious toxicity or adverse events were reported in the study.[
References:
Overview
Many widely available dietary supplements are marketed to support prostate health. African cherry (Pygeum africanum) and beta-sitosterol are two related supplements that have been studied as potential prostate cancer treatments. Note: A separate PDQ summary on PC-SPES is also available.
Several companies distribute medicinal P. africanum or beta-sitosterol as dietary supplements. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of P. africanum or beta-sitosterol as a treatment for cancer or any other medical condition.
African Cherry/Pygeum 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.[
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.[
Two components of P. africanum bark extracts, atraric acid and N-butylbenzene-sulfonamide, are androgen receptor inhibitors, as indicated by both in vitro[
Beta-Sitosterol
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.[
Research has also suggested that phytosterols may have anticarcinogenic properties, but the exact mechanisms are unknown.[
Beta-sitosterol at very high concentrations (i.e., 16 μM or 6.64 mg /mL) has been shown to significantly inhibit growth of PC-3 prostate cancer cells and induce apoptosis.[
References:
To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:
Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For an explanation of the scores and additional information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Revised text to state that in the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. Also added text to state that the quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements.
This summary is written and maintained by the
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 in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
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Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
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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:
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