The National Center for Complementary and Integrative Health NCCIH at the National Institutes of Health NIH facilitates research and evaluation of complementary and alternative practices, and provides information about a variety of approaches to health professionals and the public. NCCIH and the NIH National Library of Medicine NLM jointly developed CAM on PubMed , a free and easy-to-use search tool for finding CAM-related journal citations.

As a subset of the NLM's PubMed bibliographic database, CAM on PubMed features more than , references and abstracts for CAM-related articles from scientific journals. This database also provides links to the websites of over 1, journals, allowing users to view full-text articles. A subscription or other fee may be required to access full-text articles.

Office of Cancer Complementary and Alternative Medicine. The NCI Office of Cancer Complementary and Alternative Medicine OCCAM coordinates the activities of the NCI in the area of complementary and alternative medicine CAM.

OCCAM supports CAM cancer research and provides information about cancer-related CAM to health providers and the general public via the NCI website. National Cancer Institute NCI Cancer Information Service. residents may call the Cancer Information Service CIS , NCI's contact center, toll free at CANCER Monday through Friday from am to pm.

A trained Cancer Information Specialist is available to answer your questions. The Food and Drug Administration FDA regulates drugs and medical devices to ensure that they are safe and effective.

The Federal Trade Commission FTC enforces consumer protection laws. Publications available from the FTC include:. Prostate Cancer, Nutrition, and Dietary Supplements PDQ® —Patient Version On This Page Introduction Overview of CAM Use in Prostate Cancer Calcium: Questions and Answers Green Tea: Questions and Answers Lycopene: Questions and Answers Modified Citrus Pectin: Questions and Answers Pomegranate: Questions and Answers Selenium: Questions and Answers Soy: Questions and Answers Vitamin D: Questions and Answers Vitamin E: Questions and Answers Combination Therapies Other Prostate Health Supplements About This PDQ Summary General CAM Information Evaluation of CAM Therapies Questions to Ask Your Health Care Provider About CAM To Learn More About CAM Introduction Go to Health Professional Version.

Combined study: A combined study analyzes data from more than one study done on the same topic, such as the response to a dietary supplement, risk of getting cancer, or treatment of cancer. The results of a combined study are usually stronger than the results of any study by itself.

A combined study is also called a meta-analysis. Population study : A population study looks at a group of people who are part of the general population and share a common characteristic, such as age, sex, or health condition.

This group of people may be studied for different reasons, such as their response to a dietary supplement or risk of getting cancer. A population study is also called an epidemiologic study.

Clinical trial : A clinical trial looks at how well new medical approaches work in people. These studies may test new methods of screening , prevention , diagnosis, or treatment of cancer.

Clinical trials with a small number of people or when the treatment is not randomly assigned are not included in this summary. See the clinical trial sections of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements for information on clinical trials done using nutrients or supplements.

Laboratory and animal studies : In laboratory studies, tumor cells are used to test a substance to find out if it is likely to have any anticancer effects. In animal studies, tests are done to see if a drug , procedure, or treatment is safe and effective in animals.

Laboratory and animal studies are done before a substance is tested in people. Calcium Green Tea Lycopene Modified Citrus Pectin Pomegranate Selenium Soy Vitamin D Vitamin E Combination Therapies Other Prostate Health Supplements.

How it is given or taken. Results of studies done in people. Side effects or risks. Food and Drug Administration FDA information.

Studies of CAM use to treat prostate cancer have shown the following: Men who have prostate cancer are more likely to take dietary supplements and eat certain foods than men who do not have prostate cancer. Men who have prostate cancer and who have healthy eating habits for example, eating lots of fish rich in omega-3 fatty acids and vegetables are more likely to take dietary supplements.

Men who have prostate cancer use CAM treatments to help boost the immune system , improve quality of life , and lower the risk of the cancer coming back, but only half of them tell their doctors about their use of CAM.

A study of men with a family history of prostate cancer found that over half used vitamins or other dietary supplements for prostate health or to prevent cancer.

A study of men at a prostate cancer screening clinic found that over half took multivitamins and some took herbal supplements.

A study of prostate cancer survivors found that up to one-third took vitamins or minerals. In This Section Current Clinical Trials What is calcium? How is calcium given or taken?

Have any laboratory or animal studies been done using calcium? Have any studies of calcium been done in people? Combined studies A review found a possible link between an increased risk of prostate cancer and a diet high in dairy products and calcium.

A review of studies published between and found that milk and dairy products in the diet increased the risk of prostate cancer. A review of 45 studies found no link between dairy products and the risk of prostate cancer.

A review for the U. A review of 32 studies found that high amounts of milk, low-fat milk, cheese, total dietary calcium, and dairy calcium in the diet may increase the risk of prostate cancer. Calcium supplements and non-dairy calcium were not linked with an increased risk of prostate cancer.

Population studies of dairy products, dietary calcium, and prostate cancer risk have shown mixed results. Age, body mass index BMI , and other nutrients in dairy products may affect study results. In a randomized clinical trial reported in , men were given calcium or a placebo for 4 years and were followed for 12 years.

During the first 6 years of the study, there were fewer cases of prostate cancer in the calcium group than in the placebo group. But after 10 years, there was no difference in the number of prostate cancers between the two groups. In This Section Current Clinical Trials What is green tea? How is green tea given or taken?

Have any laboratory or animal studies been done using green tea? Have any studies of green tea been done in people? Population studies Overall, population studies suggest that green tea may help protect against prostate cancer in Asian populations. Prostate cancer deaths in Asia are among the lowest in the world.

In two randomized clinical trials in men at high risk of prostate cancer high-grade prostatic intraepithelial neoplasia [HGPIN] , those treated with green tea catechins had lower rates of prostate cancer than those treated with a placebo. A randomized clinical trial in men with HGPIN found that those treated with green tea catechins for 1 year had decreased PSA levels, though no decrease in rates of prostate cancer, compared with the placebo group.

Overall, findings suggest that green tea catechins lower PSA levels and may lower the risk of prostate cancer in men at high risk for the disease.

However, these clinical trials were limited to small numbers of people, and it is not clear if the benefits reported were from green tea.

In This Section Current Clinical Trials What is lycopene? How is lycopene given or taken? Have any laboratory or animal studies been done using lycopene? Have any studies of lycopene been done in people? Population and combined studies Some population studies in men have found that high amounts of lycopene in the diet are linked with a lower risk of prostate cancer.

Some studies have shown that lycopene levels in the blood and tissue of people with cancer are lower than in those who do not have cancer. However, other studies have not shown this.

Reviews done in and of combined studies analyzed lycopene in the diet and lycopene levels in the blood. Both reviews found that higher lycopene intake and higher blood levels of lycopene were linked with lower prostate cancer risk.

A study done in men who took part in the National Cancer Institute's Prostate, Lung, Colorectal, and Ovarian PLCO Cancer Screening Trial found no link between lycopene and tomatoes in the diet and prostate cancer risk in men with no family history of prostate cancer.

However, in men with a family history of the disease, higher amounts of lycopene in the diet were linked with a lower risk of prostate cancer. In This Section Current Clinical Trials What is modified citrus pectin? How is MCP given or taken?

Have any laboratory or animal studies been done using MCP? Have any studies of MCP been done in people? Have any side effects or risks been reported from MCP? Is MCP approved by the U. Food and Drug Administration FDA for use to prevent or treat cancer in the United States?

Current Clinical Trials Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. In This Section Current Clinical Trials What is pomegranate?

The pomegranate is made up of the following: The peel, which makes up half the fruit and contains polyphenols and minerals. The seeds. The aril the layer between the peel and the seeds , which contains phenolics and flavonoids including anthocyanins, which give the pomegranate fruit and juice a red color.

In This Section Current Clinical Trials What is selenium? How is selenium given or taken? Have any laboratory or animal studies been done using selenium? Have any studies of selenium been done in people? Combined studies A review of 15 studies found that blood selenium levels and levels of selenium measured in toenail clippings were linked to a decreased risk of prostate cancer.

One study tracking men for up to 10 years found that those who had high levels of selenium in their blood had a lower risk of prostate cancer. However, a study found that men with high selenium levels were at greater risk of being diagnosed with aggressive prostate cancer.

These differences may be due to genetic factors. The Health Professionals Follow-Up Study included 4, men with prostate cancer that had not spread to other parts of the body. The study found that taking selenium supplements after diagnosis may increase the risk of death from prostate cancer.

The study investigators recommended that men with prostate cancer use caution in taking selenium supplements. Vitamin E and a placebo. Selenium and a placebo. Vitamin E and selenium. Two placebos. In This Section Current Clinical Trials What is soy?

How is soy given or taken? Have any laboratory or animal studies been done using soy? Have any studies of soy been done in people? Combined population studies A review showed that men eating large amounts of nonfermented soy foods for example, tofu and soybean milk had a lower risk of prostate cancer.

Eating large amounts of fermented foods for example, miso was not found to affect the risk of prostate cancer. However, these results may have been affected by the way the data were collected, the types of soy taken, and genetic risk factors. In This Section Current Clinical Trials What is vitamin D?

Vitamin D has many functions in the body, such as the following: Helps absorb calcium from food in the small intestine. Improves muscle strength and immune system function. Lowers inflammation. Maintains levels of calcium and phosphate in the blood.

Helps with bone growth and protects against osteoporosis in adults. A review of 45 studies found no link between taking vitamin D and prostate cancer risk. A study found that men with low levels of sun exposure had an increased risk of prostate cancer and advanced disease.

A review of 25 studies found no link between either vitamin D in the diet or blood levels of vitamin D and the risk of prostate cancer.

A review of 21 studies found that high levels of vitamin D may be linked with a higher risk of prostate cancer. Many factors may have affected this finding. It has been proposed that men from higher income groups may have higher vitamin D levels and are more likely to get PSA testing , leading to higher rates of reported prostate cancer.

Vitamin D levels were checked every year for 5 years in men with prostate cancer that had not spread. Throughout the study, low levels of vitamin D were found in these men.

Another study in men with prostate cancer suggested that medium or high levels of vitamin D in the blood may be linked with better outcomes than lower levels. One thousand men with prostate cancer and 1, men who did not have prostate cancer were followed for up to 20 years in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.

Results suggested that men with higher blood levels of vitamin D had a greater risk of prostate cancer than men with lower vitamin D levels. In an analysis from the Selenium and Vitamin E Cancer Prevention Trial SELECT , men who had moderate blood levels of hydroxyvitamin D were found to have a lower risk of aggressive prostate cancer than men who had either lower or higher levels of hydroxyvitamin D.

A study of patterns of deaths in the United States from to showed that higher death rates from prostate cancer occurred in parts of the country with lower levels of UV radiation from sunlight. In a randomized controlled trial , vitamin D3 and omega-3 fatty acid supplements were given to prevent cancer and cardiovascular disease.

Those who took the vitamin D supplement did not have a lower rate of any cancer. A clinical trial treated patients with prostate cancer that had recurred come back with calcitriol the active form of vitamin D and naproxen for 1 year.

Results showed that after taking calcitriol and naproxen the prostate-specific antigen PSA level rose more slowly. In a study, patients with prostate cancer that did not respond to hormone therapy were treated with calcitriol and dexamethasone.

The results showed no effect on PSA levels. In a study, patients with locally advanced or metastatic prostate cancer were treated with vitamin D. The study reported that 1 in every 5 patients who took vitamin D had lower PSA levels. In This Section Current Clinical Trials What is vitamin E?

How is vitamin E given or taken? Have any studies of vitamin E been done in people? Combined population studies In a review of combined studies with about , men from several countries, higher blood levels of alpha-tocopherol were linked with a lower risk of prostate cancer.

The National Institutes of Health —American Association of Retired Persons NIH-AARP Diet and Healthy Study studied whether taking increased amounts of vitamin E in the diet and in dietary supplements could prevent prostate cancer. After 5 years, no link between vitamin E supplements and prostate cancer risk was found.

However, a lower risk of advanced prostate cancer was found in men who took high amounts of gamma-tocopherol. In a study that measured blood levels of vitamin E, the men who had prostate cancer had lower blood levels of vitamin E than those who did not have prostate cancer.

In addition, those who had higher PSA levels had lower levels of vitamin E in their blood. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study ATBC trial measured blood levels of alpha-tocopherol and dietary intake of vitamin E in men who were followed for up to 19 years.

Results showed no link between vitamin E in the diet and prostate cancer risk. However, higher levels of alpha-tocopherol in the blood may be linked with a lower risk of advanced prostate cancer.

The overall rates of prostate cancer were similar in the men who took vitamin E supplements and in those who did not. Vitamin E did not affect the number of new cases of cancer or the number of deaths from cancer. A study of men who took part in The Carotene and Retinol Efficacy Trial CARET found that, among those who were current smokers, higher blood levels of alpha-tocopherols and gamma-tocopherols were linked with lower risk of aggressive prostate cancer.

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Download options Please wait The results showed that exposing cells to EGCG for 30 minutes before radiation significantly reduced apoptosis , compared with radiation alone. According to a study, EGCG treatment 20— 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 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.

Prostate cancer cells treated with this intervention exhibited decreases in proliferation; however, the intervention did not affect nonmalignant control cells. The results suggest that this delivery system may be effective for selective targeting of prostate cancer cells.

Research also suggests that glutathione-S-transferase pi GSTP1 may be a tumor suppressor and that hypermethylation of certain regions of this gene i. Increased methylation leads to silencing of the gene.

A set of experiments investigated the effects of green tea polyphenols on GSTP1 expression. These results indicate that green tea polyphenols may have chemopreventive effects via actions on gene-silencing processes. The results of a 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. 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. 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. 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.

Treatment with EGCG resulted in reductions in tumor volume and decreases in serum PSA levels compared with vehicle treatment. In a study, TRAMP mice were started on a green tea polyphenol intervention 0.

EGCG treatment suppressed HGPIN in mice treated at age 12 weeks; however, EGCG did not prevent prostate cancer development in mice that began treatment at age 28 weeks. Furthermore, GTP consumption caused significant apoptosis, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of development, progression, and metastasis to distant organ sites.

Safety and efficacy assessments were performed at baseline and when mice were 12, 22, and 32 weeks old. Results indicated that the number and size of tumors in treated TRAMP mice were significantly decreased, compared with untreated animals.

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 a study [ 23 ] of several doses of a standardized Polyphenon E targeting TRAMP mice, no liver or other toxicities were observed.

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.

The results indicated a statistically significant inverse association between green tea consumption and prostate cancer risk in the three case-control studies, but no association was found in the four cohort studies. For black tea, no association was found between black tea consumption and prostate cancer risk.

In Asian countries with a high per capita consumption of green tea, prostate cancer mortality rates are among the lowest in the world,[ 34 ] and the risk of prostate cancer appears to be increased among Asian men who abandon their original dietary habits upon migrating to the United States.

With the increasing consumption of green tea worldwide, including by the U. population, emerging data from ongoing studies will further contribute to defining the cancer preventive activity of green tea or GTCs. Catechins other than EGCG were nondetectable or below quantifiable levels in the plasma in many trials.

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. Methylation status may be determined by polymorphisms of the catechol -O-methyltransferase COMT; the enzyme that methylates EGCG gene.

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. These findings suggest that GTCs may help prevent prostate cancer in groups at high risk of the disease.

A larger, multicenter, randomized trial NCT in the United States studied 97 men with either HGPIN or atypical small acinar proliferation who received a GTC mixture Polyphenon E, mg, bid. Because there is no clear evidence that HGPIN and atypical small acinar proliferation represent steps on a linear path to prostate cancer, these findings should be interpreted with caution.

A comparison of the estimated overall treatment effect showed a significantly greater reduction of serum PSA in men treated with Polyphenon E compared with controls Although a significant reduction in serum PSA was observed, no reduction in incidence of prostate cancer was observed in the group treated with green tea catechins compared with the placebo group.

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 an open label, phase II clinical study, prostate cancer patients scheduled for radical prostatectomy consumed four Polyphenon E tablets containing tea polyphenols, providing 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 study, 50 prostate cancer patients were randomly assigned to receive Polyphenon E 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.

Although the green tea intervention was well tolerated by most study participants, no patient had a PSA response i. In a study, patients with androgen-independent metastatic prostate cancer consumed 6 g of powdered green tea extract daily for up to 4 months.

Green tea was well tolerated by most study participants. However, six episodes of grade 3 toxicity occurred, involving insomnia , confusion , and fatigue. These results suggest that in patients with advanced prostate cancer, green tea may have limited benefits.

The safety of tea and tea compounds is supported by centuries of consumption by the human population. 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 to 1, 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.

These symptoms were mild for all but two men, who experienced severe anorexia and moderate dyspnea. Data from clinical trials [ 42 , 44 ] report long-term safety of EGCG containing GTCs, for use in men with precursor lesions of prostate cancer for prevention of prostate cancer.

One study [ 44 ] administered approximately mg EGCG per day for 1 year without any reported toxicities. trial, 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.

Although hepatotoxicity in most cases resolved within 4 months of stopping GTEs, there have been cases of positive rechallenge and liver failure requiring a liver transplant. One report described a case of acute liver failure that required a transplant in a woman who consumed GTE capsules. Because no other causal relationship could be identified, the treating physicians concluded that the fulminant liver failure experienced by this patient was most likely related to the consumption of over-the-counter GTE weight-loss supplements.

In addition, the sale of an ethanolic GTE sold as a weight-reduction aid was suspended in after reports associated hepatotoxicity four cases in Spain and nine cases in France with its use. Increased oral bioavailability occurs when GTEs are administered on an empty stomach after an overnight fast.

Increased toxicity, including hepatotoxicity, is observed when Polyphenon E or EGCG is administered to fasted dogs. The 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.

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,[ 1 ] and it also transfers light energy during photosynthesis.

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,[ 3 ] although some interventional studies have shown mixed results.

A number of in vitro and in vivo studies suggest that lycopene may also be protective against cancers of the skin, breast, lung, and liver. 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.

Therefore, premarket evaluation and approval of such supplements by the FDA are not required unless specific disease prevention or treatment claims are made.

The FDA has not approved the use of lycopene as a treatment for cancer or any other medical condition. 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.

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-hydroxymethylglutaryl-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.

Additionally, these effects in the cancer cells were observed at concentrations of lycopene that are relevant and achievable in vivo. Some studies have assessed possible beneficial interactions between lycopene and conventional cancer therapies. In one such study, various types of prostate cancer cells were treated with a combination of lycopene and docetaxel , a drug used to treat patients with castration -resistant prostate cancer, or each drug alone.

The combination treatment inhibited proliferation in four of five cell lines to a greater extent than did treatment with docetaxel alone. The findings suggest that the mechanism for these effects may involve the IGF-1 receptor IGF-1R pathway.

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.

Lycopene has also been studied for potential therapeutic effects in xenograft models. Supplementing mice with lycopene or beta-carotene resulted in decreased tumor growth. Mice exhibited longer survival times and smaller tumors when treated with a combination of docetaxel and lycopene than when they were treated with docetaxel alone.

Several 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. However, when the analysis was restricted to specific cancer types, an association was observed for other cancers RR, 0.

Likewise, a systematic review and meta-analysis evaluated lycopene dietary intake and circulating lycopene with prostate cancer risk. An inverse association between high levels of both circulating RR, 0. 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 study examined lycopene and tomato product intakes and prostate cancer risk among PLCO participants who had been followed for an average of 4. 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 results suggested no significant difference in serum lycopene concentrations between healthy participants and participants who developed prostate cancer. The Health Professionals Follow-up Study obtained dietary information and ascertained total and lethal prostate cancer cases from through January 31, Higher lycopene intake was inversely associated with total prostate cancer risk hazard ratio [HR], 0.

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. 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.

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. 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, U. Adventist men who were followed for up to 7. 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.

A number of clinical studies have been conducted investigating lycopene as a chemopreventive agent and as a potential treatment for prostate cancer. The bioavailability of lycopene has been examined and demonstrated in several studies relating lycopene to prostate cancer and other diseases.

The bioavailability of lycopene is greater in processed tomato products, such as tomato paste and tomato puree, than in raw tomatoes. It is postulated that these variations, at least in part, can be attributed to several single nucleotide polymorphisms in genes involved in red-pigment lycopene and lipid metabolism.

The end-of-study prostate lycopene concentration was 0. Prostate lycopene concentration was moderately correlated with postintervention plasma lycopene concentrations correlation coefficient, 0.

Consumption of typical servings of processed tomato products results in differing plasma and prostate lycopene concentrations. Factors including meal composition and genetics deserve further evaluation to determine their impacts on lycopene absorption, isomerization, and biodistribution.

There is evidence that dietary fat may help increase the absorption of carotenoids, including lycopene. In one experiment, healthy volunteers consumed mixed-vegetable salads with nonfat, low-fat, or full-fat salad dressing. Analysis of blood samples indicated that eating full-fat salad dressing led to more carotenoid absorption than eating low-fat or nonfat dressing.

However, this study found that combining olive oil, but not sunflower oil, with tomatoes resulted in greater plasma antioxidant activity. 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.

Sera samples collected before and after the interventions were incubated with lymph node cancer prostate cells to measure the expression of 45 target genes. In this placebo-controlled trial, circulating lycopene concentration increased only after consumption of red tomato paste and purified lycopene.

Lipid profile, antioxidant status, PSA, and IGF-1 were not modified by consumption of tomato pastes and lycopene. When prostate cancer cells were treated in vitro with sera collected from men after red tomato paste consumption, IGF binding protein-3 IGFBP-3 and the ratio of Bax to Bcl2 were up-regulated, and cyclin-D1, p53, and Nrf-2 were down-regulated compared with expression levels obtained using sera taken after the first washout period.

Intermediate gene expression changes were observed using sera collected from participants after consumption of yellow tomato paste with low carotenoid content. Cell incubation with sera from men who consumed purified lycopene led to significant up-regulation of IGFBP-3, c-fos, and uPAR compared with sera collected after placebo consumption.

These findings suggest that lycopene may not be the only factor responsible for the cancer-protective effects of tomatoes. In another study, the effect of tomato sauce on apoptosis in benign prostatic hyperplasia BPH tissue and carcinomas was examined.

Patients 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 These findings suggest that lycopene may be effective in preventing HGPIN from progressing to prostate cancer.

No statistically significant difference was observed in serum PSA levels between the two treatment groups. 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.

A number of clinical trials investigating lycopene as a potential treatment for prostate cancer are listed below in Table 2. 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 pilot study.

Mean plasma PSA levels were lower in the intervention group compared with the control group. In a phase II, randomized, placebo-controlled trial,[ 46 ] 45 men with clinically localized prostate cancer received either 15, 30, or 45 mg of lycopene Lyc-O-Mato or no supplement from time of biopsy to prostatectomy 30 days.

Plasma lycopene increased from baseline to the end of treatment in all treatment groups, with the greatest increase observed in the 45 mg lycopene-supplemented arm.

No toxicity was reported. Overall, men with prostate cancer had lower baseline levels of plasma lycopene, compared with disease-free controls, and similar to levels observed in previous studies in men with prostate cancer.

However, serum testosterone and SHBG levels in the control group remained unchanged. The mean difference between groups who received the lycopene supplementation demonstrated a lower percentage of cells expressing Ki, compared with the control group. These changes were not statistically significant, compared with the changes in the control arm for this sample size and duration of intervention.

Although antioxidant properties of lycopene have been hypothesized to be primarily responsible for its beneficial effects, this study suggests that other mechanisms mediated by steroid hormones may also be involved.

Analysis of the PSA-doubling time pretreatment vs. post-treatment showed a median increase after supplementation for days; however, this was not statistically significant.

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.

By the end of the study, serum PSA levels had almost doubled in 12 of the 17 patients, and 5 of 17 patients had achieved PSA stabilization.

Although this was a small study without a control group , the results suggest that lycopene may not be beneficial for patients with advanced prostate cancer. 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. Perhaps, future clinical trials should include longer duration of consistent lycopene exposure, while accounting for variations in individual absorption of carotenoids and heterogeneity of high-risk HGPIN, atypical small acinar proliferation and prostate cancer patient populations indolent vs.

aggressive prostate cancer or androgen-dependent vs. androgen-independent prostate cancer. Studies evaluating lycopene in randomized clinical trials targeting men at high risk for prostate cancer and populations with prostate cancer have indicated relatively few toxicities at the dose and duration of intervention.

When adverse effects occurred, they tended to present as gastrointestinal symptoms [ 49 ] and, in one study, the symptoms resolved when lycopene was taken with meals.

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. The FDA has not approved the use of MCP as a treatment for cancer or any other medical condition. In a 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 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.

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 Only a few studies have been reported on the effects of MCP in animals bearing implanted cancers and only one involving prostate cancer.

In the study, rats were given 0. The analysis revealed that treatment with 0. In a 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, The effect of MCP on prostate-specific antigen PSA doubling time PSADT was investigated in a study. Prostate cancer patients with rising PSA levels received six PeS capsules 3 times a day totaling 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.

The pomegranate tree Punica granatum L. is a member of the Punicaceae family native to Asia from Iran to northern India and cultivated throughout the Mediterranean, Southeast Asia, the East Indies, Africa, and the United States. The arils are mainly composed of water and also contain phenolics and flavonoids.

Anthocyanins, which are flavonoids present in arils, are responsible for the red color of the fruit and its juice. Research studies suggest that pomegranates have beneficial effects on a number of health conditions, including cardiovascular disease,[ 6 ] and may also have positive effects on oral or dental health.

Several companies distribute pomegranate as a dietary supplement. The FDA has not approved the use of pomegranate as a treatment or prevention for cancer or any other medical condition.

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. Ellagic acid EA was detected in the prostate following intraperitoneal, but not oral, administration of pomegranate extract 0.

Treating human prostate cancer cells with individual components of the pomegranate fruit has been shown to inhibit cell growth. Treating cells with EGCG, kaempferol, and punicic acid further resulted in apoptosis, with punicic acid a major constituent of pomegranate seeds being the strongest inducer of apoptosis.

Initial results of SELECT were published in There were no statistically significant differences in rates of prostate cancer in the four groups. 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 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.

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.

Toenail selenium concentration was inversely associated with risk of total prostate cancer odds ratio , 0. 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. A study explored the potential role of selenium in prostate cancer patients on active surveillance.

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 mg and selenomethionine 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.

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.

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. Prostate tissue is known to express estrogen receptor beta and it has been shown that the isoflavone genistein has greater affinity for estrogen receptor beta than for estrogen receptor alpha.

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. These early studies have led to a few clinical trials in humans using soy food products or supplements that targeted men with varying stages of prostate cancer.

Although these studies showed modulation of intermediate endpoints or surrogate biomarkers of prostate cancer progression, the results indicating beneficial effects from soy or soy products have been mixed.

Several companies distribute soy as a dietary supplement. The FDA has not approved the use of soy as a treatment for cancer or any other medical condition. 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.

The isoflavones were shown to down regulate growth factors involved in angiogenesis e. These findings suggest that genistein and daidzein may have chemopreventive properties.

However, during the 72 hours of incubation , only genistein provoked effects on the dynamic phenotype and decreased invasiveness in PC-3 cells. These results imply that invasive activity is at least partially dependent on membrane fluidity and that genistein may exert its antimetastatic effects by changing the mechanical properties of prostate cancer cells.

No such effects were observed for daidzein at the same dose. 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. All of the treatments resulted in decreased cell proliferation, but the greatest reductions occurred using the combination of genistein, biochanin A, and quercetin. The triple combination treatment induced more apoptosis in prostate cancer cells than did individual or doublet compound treatments.

These results indicate that combining phytoestrogens may increase the effectiveness of the individual compounds. At least one study has examined the combined effect of soy isoflavones and curcumin. Human prostate cancer cells were treated with isoflavones, curcumin, or a combination of the two.

Curcumin and isoflavones in combination were more effective in lowering PSA levels and expression of the androgen receptor than were curcumin or the isoflavones individually. Animal models of prostate cancer have been used in studies investigating the effects of soy and isoflavones on the disease.

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.

Mice fed low-dose genistein exhibited more cancer cell metastasis and greater osteopontin expression than mice fed the control or the high-dose genistein diet.

These results indicate that timing and dose of genistein treatment may affect prostate cancer outcomes and that genistein may exert biphasic control over prostate cancer. 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 , there were more metastases in secondary organs in genistein-treated mice than in vehicle-treated mice.

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. 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 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 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.

In , 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.

Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with a reduced risk of prostate cancer. Additionally, these studies failed to account for other confounding genetic or behavioral variables that may affect the risk of prostate cancer.

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.

The duration of intervention was between 6 months [ 15 ] and 1 year [ 27 , 28 ], with varying formulations of isoflavones derived from soy [ 15 , 27 ] and red clover.

Other than mild to moderate adverse events, no treatment-related toxicities were observed in all three trials. 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.

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

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.

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.

The results showed no difference between the two groups in PSA levels or in levels of metabolic and inflammatory parameters e.

Overall, isoflavones, soy, and soy products were well tolerated in clinical trials of high-risk prostate cancer patients.

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 , 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 is needed for bone growth and protects against osteoporosis in adults. Companies distribute vitamin D as a dietary supplement. The FDA has not approved the use of vitamin D as a treatment for cancer. 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,alpha-dihydroxyvitamin D3 1,D3 suppressed adhesion of prostate cancer cells in the microtube system. In addition, it was shown that 1,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,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,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,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,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. The greatest reduction in cell proliferation occurred in cells treated with VPA, 1,D3, and radiation.

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 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 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.

For more information about this study, see the Human Studies section. 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 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.

The relationship between vitamin D and prostate cancer has been examined in numerous epidemiological studies with mixed results. A meta-analysis published in 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. 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 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. Results of a meta-analysis, published in the same report, showed that men with low sun exposure had an increased risk of incident and advanced prostate cancer.

The association between dietary vitamin D or circulating concentrations of vitamin D and risk of prostate cancer has been studied. In a study of patients with prostate cancer who underwent screening and healthy controls, calcium and vitamin D intake were evaluated using food frequency questionnaires.

The study found that high calcium intake was significantly associated with higher odds of developing aggressive prostate cancer odds ratio [OR] Q1 vs. Q4, 1. This finding was statistically significant for African American men. In a cross-sectional analysis of men 88 African American patients and 31 European American patients who underwent a prostatectomy, tumor proliferation as indicated by Ki measured in prostate tissue demonstrated an inverse correlation between serum 1,25 OH 2 D and Ki 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 A meta-analysis of 19 prospective or cohort studies examined the correlation between circulating 25 OH D and the development of prostate cancer.

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, men with incident prostate cancer and 20, 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. Higher circulating 25 OH D was associated with a higher risk of nonaggressive disease OR per 80 percentile increase, 1.

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. Investigators conducted an updated two-sample mendelian randomization analysis that examined the effect of 25 OH D on prostate cancer.

Summary statistics for the outcome were extracted from the largest genome-wide association study to date that included 79, prostate cancer patients and 61, controls. Several studies have explored a possible connection between the vitamin D receptor VDR and risk of prostate cancer.

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.

Variations in the three genes were associated with changes in the risk of recurrence and progression of prostate cancer and prostate cancer mortality.

VDR correlations varied between African American and White populations. 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 patients with prostate cancer and an independent cohort of 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, prostate cancer cases and 9, controls. The pooled results showed that the Bsm1 polymorphism of vitamin D metabolism was not associated with prostate cancer risk in an overall analysis. In a Danish Prostate Cancer Registry, a total of 4, men who underwent a prostate biopsy and had a vitamin D level checked between and were monitored.

However, overall survival was lowest in men with serum vitamin D deficiency. A significantly higher prostate cancer—specific mortality hazard ratio [HR], 2. A dose -response meta-analysis of seven cohort studies with 7, participants also concluded that higher levels of 25 OH D were associated with a reduction of mortality in patients with prostate cancer.

Q1, 0. One analysis examined 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. The HR was 0. The association was further strengthened when adjusted for age at diagnosis, Gleason score , and TNM tumor, node, metastasis classification, with an HR of 0.

One hundred ninety men who participated in a large epidemiological study underwent radical prostatectomy for clinically localized prostate cancer. Men with adverse pathology had a lower median serum 25 OH D In the MARTINI-Lifestyle cohort study, biochemical recurrence BCR after radical prostatectomy was studied in 3, 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, men with prostate cancer had serum levels of plasma 25 OH D and 1,25 OH 2 D measured at 4. An analysis examined all-cause and prostate-specific mortality. A study of patients with prostate cancer examined serum levels of vitamin D and aggressive prostate cancer.

There were both positive and negative interactions between parathyroid hormone , calcium, and vitamin D and the risk of prostate cancer. These results were similar for low-risk and aggressive cases.

In a study of African American men with prostate cancer, vitamin D levels were measured at diagnosis. The genetic variant rs appeared to increase the magnitude of association between deficient serum vitamin D levels and aggressive prostate cancer OR, 3.

In a 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. Calcitriol 1,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.

The results indicated that while the treatments were well tolerated, they did not have an effect on participants' PSA levels. In a 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, Single-arm trials revealed that vitamin D supplementation had a modest effect on PSA response proportion.

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.

Muscle mass improved with high-dose vitamin D3 supplementation, but strength did not. No other measures of cancer outcomes were reported.

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, to 50, 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.

Calcitriol was the most commonly administered form of vitamin D, and adults with prostate cancer and solid tumors were the most well-represented populations in this systematic review.

Hypophosphatemia was also observed in two studies [ 49 , 50 ] that administered vitamin D in conjunction with docetaxel in men with prostate cancer.

The authors concluded that no adverse effects were experienced beyond what was expected from high-dose calcitriol supplementation and was denoted as having a low risk of interaction. 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.

Most of the side effects were expected toxicities related to the chemotherapy. Grade 2 hypercalcemia was observed in one patient. Administration of calcitriol was discontinued until hypercalcemia resolved. Supplementation was restarted after 2 weeks.

In another patient, persistent grade 3 fatigue was observed, and treatment of calcitriol was discontinued as docetaxel was reduced. Phase I studies have looked at the maximum tolerated dose MTD of weekly intravenous and oral calcitriol in conjunction with various chemotherapy drugs for cancer treatment.

Grade 2 hypercalcemia was observed in two of four patients receiving 96 μg per week 3, IU of calcitriol and was denoted nontolerable.

No significant bone marrow suppression was observed at any dose. A dose of 74 μg 3, IU per week was denoted as the MTD. The study suggests no major interaction between calcitriol and gefitinib. A second phase I study examined the MTD and pharmacokinetics of calcitriol when administered with paclitaxel over the course of 6 weeks.

Results demonstrate that very high doses of calcitriol can be safely administered with paclitaxel. However, it is important to note that participants were administered from 8 to 76 capsules of calcitriol with no report of adherence to the prescribed dose of calcitriol.

Vitamin E was discovered in 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-.

Most dietary vitamin E comes from gamma-tocopherol. Food sources of vitamin E include vegetable oil, nuts, and egg yolks. The bioavailability of vitamin E depends on a number of factors, such as the food matrix containing vitamin E e.

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. The FDA has not approved the use of vitamin E as a treatment for cancer. 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 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. Clin Chim Acta ; Chtourou Y, Fetoui H, Jemai R, et al. Naringenin reduces cholesterol induced hepatic inflammation in rats by modulating matrix metalloproteinases-2, 9 via inhibition of nuclear factor κB pathway.

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Our findings suggest that GL is an effective anti-cancer agent that may potentially serve as a novel therapeutic option for prostate cancer treatment.

Abstract Prostate cancer is one of the most prevalent malignancies and is the second leading cause of cancer-related deaths in men. Publication types Research Support, Non-U.