This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
This complementary and alternative medicine (CAM) information summary provides an overview of the use of various foods and dietary supplements for reducing the risk of developing prostate cancer or for treating prostate cancer. This summary includes history of research on different foods and dietary supplements, reviews of laboratory and animal studies , and results of clinical trials. Each type of dietary supplement and food will have a dedicated section in the summary and new topics will be added over time.
Prostate cancer is the most common noncutaneous cancer affecting men in the United States. From 2004 to 2008, the median age of diagnosis of prostate cancer was 67, and the incidence rate was 156 cases per 100,000 men per year.
Many studies suggest that CAM use is common among prostate cancer patients, and the use of vitamins , supplements, and specific foods is frequently reported by these patients. For example, the Prostate CAncer Therapy Selection (PCATS) study was a prospective study investigating 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 the patients with the healthiest dietary patterns (e.g., high consumption of fatty fish and vegetables). In a Canadian study, CAM use was reported among 39% of recently diagnosed prostate cancer patients, and the most commonly used forms of CAM were herbals , vitamins, and minerals . Within those categories, saw palmetto , vitamin E , and selenium were the most popular. The two most popular reasons for choosing CAM were to boost the immune system and to prevent recurrence . According to another Canadian study, approximately 30% of survey respondents with prostate cancer reported using CAM treatments. In that study, vitamin E, saw palmetto, and lycopene were the most commonly used. A British study published in 2008 indicated that 25% of prostate cancer patients used CAM, with the most frequently reported interventions being low-fat diets , vitamins, and lycopene. The majority of CAM users in this study cited improving quality of life and boosting the immune system as the main reasons they used CAM.
Vitamin and supplement use has also been documented in men at risk of developing prostate cancer. One study examined vitamin and supplement use in men with a family history of prostate cancer. At the time of the survey, almost 60% of the men were using vitamins or supplements. One third of the men were using vitamins and supplements that were specifically marketed for prostate health or chemoprevention (e.g., selenium, green tea, and saw palmetto). A 2004 study examined herbal and vitamin supplement use in men attending a prostate cancer screening clinic. Men attending the screening clinic completed questionnaires about supplement use. Of the respondents, analysis revealed that 70% used multivitamins, and 21% reported using herbal supplements.
A meta-analysis published in 2008 reviewed studies reporting vitamin and mineral supplement use among cancer survivors. The results showed that, among prostate cancer survivors, vitamin or mineral use ranged from 26% to 35%.
Although many prostate cancer patients use CAM treatments, they do not all disclose their CAM use to treating physicians. According to results from the PCATS study, 43% of patients discussed their CAM use with a healthcare professional. In two separate studies, 58% of respondents told their doctors about their CAM usage.[4,6]
How do prostate cancer patients decide whether to use CAM or not? A qualitative study published in 2005 described results from interviews with prostate cancer patients who were CAM users or nonusers. The study identified differences in thinking patterns between the two groups and suggested that no specific theme led patients to CAM, rather a combination of ideas directed them. For example, the perception of CAM being harmless was associated with the belief that conventional medicine resulted in many negative side effects. Results of a 2003 qualitative study suggest that decision making by prostate cancer patients about CAM treatments depends on both fixed (e.g., medical history) and flexible (e.g., a need to feel in control) decision factors.
|1.||National Cancer Institute.: SEER Stat Fact Sheets: Prostate. Bethesda, MD: National Cancer Institute, 2011. Available online. Last accessed December 14, 2011.|
|2.||McDermott CL, Blough DK, Fedorenko CR, et al.: Complementary and alternative medicine use among newly diagnosed prostate cancer patients. Support Care Cancer 20 (1): 65-73, 2012.|
|3.||Westerlund A, Steineck G, Bälter K, et al.: Dietary supplement use patterns in men with prostate cancer: the Cancer Prostate Sweden study. Ann Oncol 22 (4): 967-72, 2011.|
|4.||Eng J, Ramsum D, Verhoef M, et al.: A population-based survey of complementary and alternative medicine use in men recently diagnosed with prostate cancer. Integr Cancer Ther 2 (3): 212-6, 2003.|
|5.||Boon H, Westlake K, Stewart M, et al.: Use of complementary/alternative medicine by men diagnosed with prostate cancer: prevalence and characteristics. Urology 62 (5): 849-53, 2003.|
|6.||Wilkinson S, Farrelly S, Low J, et al.: The use of complementary therapy by men with prostate cancer in the UK. Eur J Cancer Care (Engl) 17 (5): 492-9, 2008.|
|7.||Bauer CM, Ishak MB, Johnson EK, et al.: Prevalence and Correlates of Vitamin and Supplement Usage Among Men With a Family History of Prostate Cancer. Integr Cancer Ther : , 2011.|
|8.||Barqawi A, Gamito E, O'Donnell C, et al.: Herbal and vitamin supplement use in a prostate cancer screening population. Urology 63 (2): 288-92, 2004.|
|9.||Velicer CM, Ulrich CM: Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review. J Clin Oncol 26 (4): 665-73, 2008.|
|10.||Singh H, Maskarinec G, Shumay DM: Understanding the motivation for conventional and complementary/alternative medicine use among men with prostate cancer. Integr Cancer Ther 4 (2): 187-94, 2005.|
|11.||Boon H, Brown JB, Gavin A, et al.: Men with prostate cancer: making decisions about complementary/alternative medicine. Med Decis Making 23 (6): 471-9, 2003 Nov-Dec.|
This section contains the following key information:
General Information and History
Lycopene is a carotenoid, a natural pigment made by plants, which helps to protect plants from stress, and it also transfers light energy during photosynthesis. Lycopene is found in a number of fruits and vegetables, including apricots, guava, and watermelon, but the majority of lycopene consumed in the United States is from tomato-based products. The bioavailability of lycopene is greater in processed tomato products, such as tomato paste and tomato puree, than it is in raw tomatoes. When ingested , lycopene is broken down into a number of metabolites and is thought to have various biological functions, including antioxidant capabilities and a role in gap-junction communication.
There is evidence that dietary fat may help increase the absorption of carotenoids, including lycopene. In one experiment, healthy volunteers consumed mixed-vegetable salads with nonfat, low-fat, or full-fat salad dressing. Analysis of blood samples indicated that eating full-fat salad dressing led to more carotenoid absorption than eating low-fat or nonfat dressing. Results of a randomized study published in 2005 revealed that cooking diced tomatoes with olive oil significantly increased lycopene absorption compared to cooking tomatoes without olive oil. According to one study, there was no difference in plasma lycopene levels following consumption of tomatoes mixed with olive oil or tomatoes mixed with sunflower oil, suggesting that absorption of lycopene may not be dependent on the type of oil used. However, this same study found that combining olive oil, but not sunflower oil, with tomatoes resulted in greater plasma antioxidant activity.
Lycopene has been investigated for its role in chronic diseases, including cardiovascular disease and cancer. Numerous epidemiological studies suggest that lycopene may help prevent cardiovascular disease, although some interventional studies have shown mixed results. 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. However, epidemiological studies reported to date have yielded inconsistent findings regarding lycopene's potential in reducing cancer risk. The few human intervention trials have been small and generally focused on intermediate endpoints and thus have not been definitive.[2,10]
In 2004, the Food and Drug Administration (FDA) received two petitions for qualified health claims regarding tomatoes, lycopene, and reduced cancer risk. In a 2007 review, the FDA concluded there was not enough evidence to support a claim that lycopene helps reduce cancer risk. The FDA found there was no evidence of a link between tomato consumption and lung, colorectal, breast, cervical, or endometrial cancers, and there was limited evidence for an association between tomato consumption and reduced risks of prostate, ovarian, gastric, and pancreatic cancers.
In vitro studies
Many in vitro studies have been conducted examining a link between lycopene and prostate cancer.
Treating normal human prostate epithelial cells with lycopene resulted in dose-dependent growth inhibition, indicating that inhibition of prostate cell proliferation may be one way lycopene may lower the risk of prostate cancer.
In addition, treating prostate cancer cells with lycopene resulted in a significant decrease in the number of lycopene-treated cells in S phase of the cell cycle, suggesting that lycopene may lower cell proliferation by altering cell-cycle progression. Moreover, apo-12'-lycopenal, a lycopene metabolite, also reduced prostate cancer cell proliferation and may also modulate cell-cycle progression.
Some studies have suggested that cancer cells have altered cholesterol-biosynthesis pathways. Treating prostate cancer cells with lycopene resulted in dose-dependent decreases in 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (the rate-limiting enzyme in cholesterol synthesis), total cholesterol, and cell growth and an increase in apoptosis . However, adding mevalonate prevented the growth-inhibitory effects of lycopene, indicating that the mevalonate pathway may be important to the anti-cancer activity of lycopene. Lycopene may also affect cholesterol levels in prostate cancer cells by activating the peroxisome proliferator-activated receptor gamma (PPARγ)-liver X receptor alpha (LXRα)-ABCA1 pathway, which leads to decreased cholesterol levels and may ultimately result in decreased cell proliferation. ABCA1 mediates cholesterol efflux, and PPARγ has been shown to inhibit the growth and differentiation of prostate cancer cells. In one study, treating prostate cancer cells with lycopene resulted in increased expression of PPARγ, LXRα, and ABCA1 as well as lower total cholesterol. In addition, when the cells were treated with a PPARγ antagonist, cell proliferation increased while treating cells with a combination of the PPARγ antagonist and lycopene decreased cell proliferation.
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.
Some studies have assessed possible beneficial interactions between lycopene and conventional cancer therapies. In one such study, various types of prostate cancer cells were treated with a combination of lycopene and docetaxel , a drug used to treat patients with castration-resistant prostate cancer, or each drug alone. The combination treatment inhibited more cell growth in four of five cell types examined than treatment with docetaxel alone. The findings suggest that the mechanism for these effects may involve the insulin-like growth factor-1 receptor (IGF-1R) pathway.
In a chemoprevention study , 59 transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed diets supplemented with tomato paste or lycopene beadlets (both preparations contained 28 mg lycopene/kg chow). Mice that received lycopene beadlets exhibited a larger reduction in prostate cancer incidence compared to control mice than mice supplemented with tomato paste, suggesting that lycopene beadlets may provide greater chemopreventive effects than tomato paste.
Ketosamines are carbohydrate derivatives formed when food is dehydrated. In one study, FruHis (a ketosamine in dehydrated tomatoes) combined with lycopene resulted in greater growth inhibition of implanted rat prostate cancer cells than did lycopene or FruHis alone. In addition, in a N-methyl-N-nitrosourea (NMU)/testosterone-induced prostate carcinogenesis model, rats fed a tomato paste and FruHis diet had longer survival times than rats fed only with tomato paste or tomato powder.
Lycopene has also been studied for potential therapeutic effects in xenograft studies. In one study, athymic nude mice were injected with human prostate cancer cells and were treated with either lycopene (4 mg/kg body weight or 16 mg/kg body weight) or beta-carotene (16 mg/kg body weight). Supplementing mice with lycopene or beta carotene resulted in decreased tumor growth. In another study, nude mice were injected with human prostate cancer cells and treated with intraperitoneal injections of docetaxel, lycopene (15 mg/kg per day) administered via gavage, or a combination of both. Mice exhibited longer survival times and smaller tumors when treated with a combination of docetaxel and lycopene than when they were treated with docetaxel alone.
Several epidemiologic studies have assessed potential associations between lycopene intake and prostate cancer incidence.
A possible link between serum lycopene concentrations and prostate cancer risk was investigated in a study using data obtained from the Prostate Cancer Prevention Trial (PCPT); however, the analysis failed to demonstrate such a connection.
An association between lycopene serum concentration and risk of cancer was also examined in men participating in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study in Finland. 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 but not prostate cancer.
A 2004 meta-analysis of studies investigating tomato intake and prostate cancer risk found a small positive effect of tomato products on risk reduction.
The National Cancer Institute's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial has been a source of subjects for studies examining an association between lycopene intake and prostate cancer risk. A 2006 study examined lycopene and tomato product intakes and prostate cancer risk among the trial's participants. Lycopene and tomato product intakes were assessed via Food Frequency Questionnaires. Overall, no association was found between dietary intake of lycopene or tomato products and the risk of prostate cancer. However, among men with a family history of prostate cancer, increased lycopene consumption was associated with decreased prostate cancer risk. A follow-up study was conducted that examined serum lycopene and risk of prostate cancer in the same group of PLCO participants. The results suggest that there was no significant difference in serum lycopene concentrations between healthy participants and participants who developed prostate cancer.
A number of clinical studies have been conducted investigating lycopene as a chemopreventive agent and as a potential treatment for prostate cancer.
Healthy males participated in a crossover design study that attempted to differentiate the effects of tomatoes from those of lycopene. After study entry, the participants consumed their usual diet for 1 week followed by a 2-week washout period on a lycopene-free diet. Next, they were randomly assigned to consume either yellow tomato paste (0 mg/day lycopene) (Group 1) or red tomato paste (16 mg/day lycopene) (Group 2) for 1 week as part of their regular diets, followed by a second 2-week washout period. Then, the participants in Group 1 crossed over to red tomato paste, and the participants in Group 2 crossed over to yellow tomato paste for 1 week as part of their regular diets, followed by a third 2-week washout period. Finally, the participants in Group 1 took a capsule of lycopene (16 mg/day) and the participants in Group 2 took a placebo daily for 1 week. Circulating lycopene levels increased only after consumption of red tomato paste and the lycopene capsules. Changes in serum prostate-specific antigen (PSA) level, antioxidant status, and insulin-like growth factor I level were not modified by the consumption of tomato paste and lycopene. When prostate cancer cells were treated in vitro with sera collected from participants after red tomato paste consumption, insulin-like growth factor binding protein-3 (IGFBP-3) and the ratio of Bax to Bcl2 were up-regulated, and cyclin-D1, p53 , and Nrf-2 were down-regulated compared to expression levels obtained using sera taken after the first washout period. Intermediate gene expression changes were observed using sera collected from participants after yellow tomato paste consumption. These findings suggest that lycopene may not be the only factor responsible for the protective effects of tomatoes.
In another study, the effect of tomato sauce on apoptosis in benign prostate hyperplasia (BPH) tissue and carcinomas was examined. Patients who were scheduled for prostatectomy were given tomato sauce pasta entrees (30 mg/day of lycopene) to eat daily for 3 weeks before surgery . Patients scheduled for surgery who did not receive the tomato sauce pasta entrees served as control subjects. Those who consumed the tomato sauce pasta entrees exhibited decreased serum PSA levels and increased apoptotic cell death in BPH tissue and carcinomas.
In a third study, patients with high-grade prostate intraepithelial neoplasia (HGPIN) received 4 mg of lycopene twice a day or no lycopene supplementation for 2 years. A greater decrease in serum PSA levels was observed in those treated with lycopene supplements compared with those who did not take the supplementation. During follow-up, adenocarcinomas occurred more often in patients who had not received the supplements than in patients who had received lycopene. These findings suggest that lycopene may be effective in preventing HGPIN from progressing to prostate cancer. In another study, men at high risk of prostate cancer (e.g., HGPIN) were randomly assigned to receive a daily multivitamin (that did not contain lycopene) or the same multivitamin and a lycopene supplement (30 mg/day) for 4 months. No statistically-significant difference was observed in serum PSA levels between the two treatment groups. These findings suggest that, although lycopene supplements may be safe to take for at least 4 months, they may not affect PSA levels.
Other studies have examined the potential therapeutic effect of lycopene-containing products in patients with prostate cancer. The effects of lycopene supplementation on prostate tissue and prostate cancer biomarkers were investigated in patients with localized prostate cancer in a 2002 pilot study . Patients received lycopene supplements (30mg/day) or no intervention twice daily for 3 weeks prior to radical prostatectomy . Patients who received the lycopene supplements had smaller tumors and lower serum PSA levels than patients who did not receive the supplements. These results suggest that lycopene may be beneficial in prostate cancer treatment. A 2006 study investigated whether lycopene supplements (10 mg/day) would affect PSA velocity in patients with localized prostate cancer. There was a statistically significant decrease in PSA velocity following lycopene treatment as well as a large, but not statistically significant, increase in PSA doubling time.
In one study, prostate cancer patients who had biochemical relapse following radiation therapy or surgery received lycopene supplements twice daily for 1 year. There were six cohorts in the study, each receiving a different dose of lycopene (15, 30, 45, 60, 90, or 120 mg/day). Serum PSA levels did not respond to lycopene treatment. Plasma lycopene levels rose and appeared to plateau by 3 months for all doses. The results indicate that, although lycopene may be safe and well tolerated, it did not alter serum PSA levels in biochemically relapsed prostate cancer patients.
In a 2004 open-label study , patients with hormone-refractory prostate cancer (HRPC) received lycopene supplements daily (10 mg/day of lycopene) for 3 months. Of the study's participants, 50% had PSA levels that remained stable, 15% showed biochemical progression, 30% showed a partial response , and one patient (5% of the total sample) exhibited a complete response after treatment. These findings suggest that lycopene supplements may be safe and effective for patients with HRPC. In a phase II study, HRPC patients took lycopene supplements daily (15 mg of lycopene/day) for 6 months. By the end of the study, serum PSA levels had almost doubled in 12 of the 17 patients, and 5 of 17 patients had achieved PSA stabilization. Although this was a small study without a control group, the results suggest that lycopene may not be beneficial for patients with advanced prostate cancer.
In another study, patients with androgen-independent prostate cancer consumed either tomato paste or tomato juice daily (both preparations provided 30 mg of lycopene/day) for at least 4 months. Only one patient in this study exhibited a decrease in PSA level, suggesting that lycopene may not be effective therapy for patients with androgen-independent prostate cancer. A number of participants experienced gastrointestinal side effects after eating the tomato paste or drinking the tomato juice.
In one 2011 study, men with low-risk prostate cancer were randomly assigned to receive lycopene (30 mg of lycopene/day), fish oil (3 gm of fish oil capsules/day) supplements, or a placebo daily for 90 days. Gene expression analysis showed no statistically significant differential expression of individual genes associated with the consumption of fish oil or lycopene supplements. However, pathway analysis revealed that an oxidative stress response pathway was significantly modulated following lycopene or fish oil supplement use compared with placebo (fish oil: P = .01, lycopene: P = .001).
Current Clinical Trials
Check NCI's list of cancer clinical trials for CAM clinical trials on lycopene for prostate cancer that are actively enrolling patients.
General information about clinical trials is also available from the NCI Web site.
Lycopene has been well tolerated in a number of clinical trials involving prostate cancer patients.[26,28,29,31,33] When adverse effects occurred, they tended to present as gastrointestinal symptoms and, in one study, the symptoms resolved when lycopene was taken with meals. Another study reported that one participant withdrew because of diarrhea.
The U.S. Food and Drug Administration (FDA) has accepted the determination by various companies that their lycopene-containing products meet the FDA's requirements for the designation of Generally Recognized as Safe (GRAS).
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|6.||Fielding JM, Rowley KG, Cooper P, et al.: Increases in plasma lycopene concentration after consumption of tomatoes cooked with olive oil. Asia Pac J Clin Nutr 14 (2): 131-6, 2005.|
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|12.||Obermüller-Jevic UC, Olano-Martin E, Corbacho AM, et al.: Lycopene inhibits the growth of normal human prostate epithelial cells in vitro. J Nutr 133 (11): 3356-60, 2003.|
|13.||Ford NA, Elsen AC, Zuniga K, et al.: Lycopene and apo-12'-lycopenal reduce cell proliferation and alter cell cycle progression in human prostate cancer cells. Nutr Cancer 63 (2): 256-63, 2011.|
|14.||Palozza P, Colangelo M, Simone R, et al.: Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines. Carcinogenesis 31 (10): 1813-21, 2010.|
|15.||Yang CM, Lu IH, Chen HY, et al.: Lycopene inhibits the proliferation of androgen-dependent human prostate tumor cells through activation of PPARγ-LXRα-ABCA1 pathway. J Nutr Biochem 23 (1): 8-17, 2012.|
|16.||Zhang X, Wang Q, Neil B, et al.: Effect of lycopene on androgen receptor and prostate-specific antigen velocity. Chin Med J (Engl) 123 (16): 2231-6, 2010.|
|17.||Tang Y, Parmakhtiar B, Simoneau AR, et al.: Lycopene enhances docetaxel's effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels. Neoplasia 13 (2): 108-19, 2011.|
|18.||Konijeti R, Henning S, Moro A, et al.: Chemoprevention of prostate cancer with lycopene in the TRAMP model. Prostate 70 (14): 1547-54, 2010.|
|19.||Mossine VV, Chopra P, Mawhinney TP: Interaction of tomato lycopene and ketosamine against rat prostate tumorigenesis. Cancer Res 68 (11): 4384-91, 2008.|
|20.||Yang CM, Yen YT, Huang CS, et al.: Growth inhibitory efficacy of lycopene and β-carotene against androgen-independent prostate tumor cells xenografted in nude mice. Mol Nutr Food Res 55 (4): 606-12, 2011.|
|21.||Kristal AR, Till C, Platz EA, et al.: Serum lycopene concentration and prostate cancer risk: results from the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 20 (4): 638-46, 2011.|
|22.||Karppi J, Kurl S, Nurmi T, et al.: Serum lycopene and the risk of cancer: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study. Ann Epidemiol 19 (7): 512-8, 2009.|
|23.||Etminan M, Takkouche B, Caamaño-Isorna F: The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev 13 (3): 340-5, 2004.|
|24.||Kirsh VA, Mayne ST, Peters U, et al.: A prospective study of lycopene and tomato product intake and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 15 (1): 92-8, 2006.|
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|28.||Mohanty NK, Saxena S, Singh UP, et al.: Lycopene as a chemopreventive agent in the treatment of high-grade prostate intraepithelial neoplasia. Urol Oncol 23 (6): 383-5, 2005 Nov-Dec.|
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|32.||Clark PE, Hall MC, Borden LS Jr, et al.: Phase I-II prospective dose-escalating trial of lycopene in patients with biochemical relapse of prostate cancer after definitive local therapy. Urology 67 (6): 1257-61, 2006.|
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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 and also in the formulation of oral and topical medicines as a stabilizer and nonbiodegradable matrix to support controlled drug delivery. Citrus pectin is found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature. Modification results in shorter molecules that dissolve better in water and are more readily absorbed by the body than are complex, longer chain citrus pectins. One of the molecular targets of MCP is galectin-3, a protein found on the surface and within mammalian cells that is involved in many cellular processes, including cell adhesion, cell activation and chemoattraction, cell growth and differentiation, the cell cycle , and apoptosis; MCP inhibits galectin-3 activity.
Some research suggests that MCP may be protective against various types of cancer, including colon , lung , and prostate cancer. MCP may exert its anticancer effects by interfering with tumor cell metastasis or by inducing apoptosis.
MCP was also shown to activate natural killer cells in leukemic cell cultures, suggesting it may be able to stimulate the immune system.
Preclinical Studies/Animal Studies
In vitro studies
In a 2007 study, pectins were investigated for their anticancer properties. Prostate cancer cells were treated with three different pectins; citrus pectin (CP), Pectasol (PeS, a dietary supplement containing modified citrus pectin), and fractionated pectin powder (FPP). FPP induced apoptosis to a much greater degree than did CP and PeS. Further analysis revealed that treating prostate cancer cells with heated CP resulted in levels of apoptosis similar to those following treatment with FPP. This suggests that specific structural features of pectin may be responsible for its ability to induce apoptosis in prostate cancer cells.
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 another study, the role of galectin-3, a multifunctional endogenous lectin , in cisplatin -treated prostate cancer cells was examined. Prostate cancer cells that expressed galectin-3 were found to be resistant to the apoptotic effects of cisplatin. However, cells that did not express galectin-3 (via silencing RNA knockdown of galectin-3 expression or treatment with MCP) were susceptible to cisplatin-induced apoptosis. These findings suggest that galectin-3 expression may play a role in prostate cancer cell chemoresistance and that the efficacy of cisplatin treatment in prostate cancer may be improved by inhibiting galectin-3.
Only a few studies have been reported on the effects of MCP in animals bearing implanted cancers and only one involving prostate cancer.[8,9] The prostate cancer study examined the effects of MCP on the metastasis of prostate cancer cells injected into rats. In the study, rats were given 0.0%, 0.01%, 0.1%, or 1.0% MCP (wt/vol) in their drinking water beginning 4 days after cancer cell injection. The analysis revealed that treatment with 0.1% and 1.0% MCP resulted in statistically significant reductions in lung metastases but did not affect primary tumor growth.
In a 2007 pilot study , patients with advanced solid tumors (various types of cancers were represented, including prostate cancer) received MCP (5 g MCP powder dissolved in water) 3 times a day for at least 8 weeks. Following treatment, improvements were reported in some measures of quality of life , including physical functioning, global health status, fatigue , pain, and insomnia . In addition, 22.5% of participants had stable disease after 8 weeks of MCP treatment, and 12.3% of participants had disease stabilization lasting more than 24 weeks.
The effect of MCP on prostate-specific antigen (PSA) doubling time (PSADT) was investigated in a 2003 study. Prostate cancer patients with rising PSA levels received six PeS capsules 3 times a day (totaling 14.4 g of MCP powder daily) for 12 months. Following treatment, 7 of 10 patients had a statistically significant (P ≤ .05) increase in PSADT.
In one prospective pilot study , MCP was well tolerated by the majority of treated patients, with the most commonly reported side effects being pruritus , dyspepsia , and flatulence. In another study, no serious side effects from MCP were reported, although three patients withdrew from the study due to abdominal cramps and diarrhea that improved once treatment was halted.
|1.||Mohnen D: Pectin structure and biosynthesis. Curr Opin Plant Biol 11 (3): 266-77, 2008.|
|2.||Glinsky VV, Raz A: Modified citrus pectin anti-metastatic properties: one bullet, multiple targets. Carbohydr Res 344 (14): 1788-91, 2009.|
|3.||Azemar M, Hildenbrand B, Haering B, et al.: Clinical benefit in patients with advanced solid tumors treated with modified citrus pectin: a prospective pilot study. Clin Med Oncol 1: 73-80, 2007. Available online. Last accessed February 2, 2012.|
|4.||Jackson CL, Dreaden TM, Theobald LK, et al.: Pectin induces apoptosis in human prostate cancer cells: correlation of apoptotic function with pectin structure. Glycobiology 17 (8): 805-19, 2007.|
|5.||Ramachandran C, Wilk BJ, Hotchkiss A, et al.: Activation of human T-helper/inducer cell, T-cytotoxic cell, B-cell, and natural killer (NK)-cells and induction of natural killer cell activity against K562 chronic myeloid leukemia cells with modified citrus pectin. BMC Complement Altern Med 11: 59, 2011.|
|6.||Yan J, Katz A: PectaSol-C modified citrus pectin induces apoptosis and inhibition of proliferation in human and mouse androgen-dependent and- independent prostate cancer cells. Integr Cancer Ther 9 (2): 197-203, 2010.|
|7.||Wang Y, Nangia-Makker P, Balan V, et al.: Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment. Cell Death Dis 1: e101, 2010.|
|8.||Hayashi A, Gillen AC, Lott JR: Effects of daily oral administration of quercetin chalcone and modified citrus pectin on implanted colon-25 tumor growth in Balb-c mice. Altern Med Rev 5 (6): 546-52, 2000.|
|9.||Pienta KJ, Naik H, Akhtar A, et al.: Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst 87 (5): 348-53, 1995.|
|10.||Guess BW, Scholz MC, Strum SB, et al.: Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study. Prostate Cancer Prostatic Dis 6 (4): 301-4, 2003.|
This section contains the following key information:
General Information and History
The pomegranate (Punica granatum L.) is a member of the Punicaceae family native to Asia (from Iran to northern India) and cultivated throughout the Mediterranean, Southeast Asia, East Indies, Africa, and the United States. The history of the pomegranate goes back centuries — the fruit is considered sacred by many religions and has been used for medicinal purposes since ancient times. The fruit is comprised of peel (pericarp), seeds, and aril (outer layer surrounding the seeds). The peel makes up 50% of the fruit and contains a number of bioactive compounds , including phenolics, flavonoids, and ellagitannins, and minerals such as potassium , magnesium , and sodium. Arils are mainly composed of water and also contain phenolics and flavonoids. Anthocyanins, which are the most abundant flavonoid present in arils, are responsible for the fruit's and its juice's red color. The majority of antioxidant activity comes from ellagitannins.
Preclinical Studies/Animal Studies
Research studies in the laboratory have examined the effects of pomegranate on many prostate cancer cell lines and in rodent models of the disease.
In vitro studies
Ellagitannins (the main polyphenols in pomegranate juice) are hydrolyzed to ellagic acid , and then to urolithin A (UA) derivatives. According to a tissue distribution experiment in wild-type mice, the prostate gland rapidly takes up high concentrations of UA after oral or intraperitoneal administration (0.3mg/mouse/dose). Ellagic acid was detected in the prostate following intraperitoneal, but not oral, administration of pomegranate extract (0.8mg/mouse/dose).
Treating human prostate cancer cells with individual components of the pomegranate fruit has been shown to inhibit cell growth.[8,9,10,11] In one study, dihydrotestosterone -stimulated LNCaP cells were treated with 13 pomegranate compounds at various concentrations (0-100 µM). Four of the 13 compounds, epigallocatechin gallate (EGCG), delphinidin chloride, kaempferol, and punicic acid, exhibited an ability to inhibit cell growth in a dose-dependent manner. Treating cells with EGCG, kaempferol, and punicic acid further resulted in apoptosis, with punicic acid (the primary constituent of pomegranate seeds) being the strongest inducer of apoptosis. Additionally, findings from this study suggest that punicic acid may activate apoptosis by a caspase-dependent pathway.
Pomegranate extracts have also been shown to inhibit the proliferation of human prostate cancer cells in vitro.[10,12,13] In one study, three prostate cancer cell lines (LNCaP, LNCaP-AR, and DU-145 ) were treated with pomegranate polyphenols [punicalagin (PA) or ellagic acid (EA)], a pomegranate extract (POMx, which contains EA and PA), or pomegranate juice (PJ, which contains PA, EA, and anthocyanins) in concentrations ranging from 3.125 to 50 µg/mL. All four treatments resulted in statistically significant increases in apoptosis and dose-dependent decreases in cell proliferation in the three cell lines. However, PJ and POMx were stronger inhibitors of cell growth than were PA and EA. In this study, the effects of PA, EA, POMx, and PJ on the expression of androgen -synthesizing enzyme genes and the androgen receptor were also measured. Although statistically significant decreases in gene expression occurred in LNCaP cells following treatment with POMx and in DU-145 cells following treatment with EA and POMx, significant decreases in gene expression and androgen receptor occurred in LNCaP-AR cells following all of the treatments. In another study, treating PC3 cells (human prostate cancer cells with a high metastatic potential) with POMx (10-100 µg/mL) resulted in cell growth inhibition and apoptosis, both in a dose-dependent manner. Treatment of CWR22Rv1 cells (prostate cancer cells that express the androgen receptor and secrete PSA) with POMx (10-100 µg/mL) led to the inhibition of cell growth, a dose-dependent decrease in androgen receptor protein expression, and dose-dependent reductions in PSA protein levels.
The enzyme cytochrome P450 (CYP1B1) has been implicated in cancer development and progression. As a result, CYP1B1 inhibitors may be effective anti-carcinogenic targets. In a study reported in 2009, the effects of pomegranate metabolites on CYP1B1 activation and expression in CWR22Rv1 prostate cancer cells were examined. In this study, urolithins A and B inhibited CYP1B1 expression and activity.
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) or IGFBP-3 (1 µg/mL) 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 suggest that PJ may be beneficial in slowing down or preventing cancer cell metastasis.
The effects of pomegranate on prostate cancer have been examined using a number of rodent models of the disease. In one study, athymic nude mice were injected with tumor-forming cells. Following inoculation, animals were randomly assigned to receive normal drinking water or PJ (0.1% or 0.2% POMx in drinking water, which resulted in an intake corresponding to 250 or 500 mL of PJ per day for an average adult human). Small, solid tumors appeared earlier in mice drinking normal water only than in mice drinking PJ (8 days vs. 11-14 days). Moreover, tumor growth rates were significantly reduced in mice drinking PJ compared with mice drinking normal water only. Animals drinking PJ also exhibited significant reductions in serum PSA levels compared with animals drinking normal water only. In other studies, treatment with a POMx resulted in decreased tumor volumes in SCID mice that had been injected with prostate cancer cells.[7,16]
Similarly, when nude mice were injected with pomegranate seed oil (2 µg/g body weight), pomegranate pericarp (peel) polyphenols (2 µg/g body weight), or saline 5 to 10 minutes prior to being implanted with solid prostate cancer tumors, mice injected with the pomegranate extracts had significantly smaller tumor volumes compared with the mice injected with saline (P < .001).
In another study, which was reported in 2011, 6-week-old transgenic adenocarcinoma of the mouse prostate (TRAMP) mice received normal drinking water or PJ (0.1% or 0.2% POMx in drinking water) for 28 weeks. The results showed that 100% of the mice that received water only developed tumors by 20 weeks of age, whereas just 30% and 20% of the mice that received 0.1% and 0.2% PJ, respectively, developed tumors. By 34 weeks of age, 90% of the water-fed mice exhibited metastases to distant organs whereas only 20% of the mice that received pomegranate juice showed metastasis. The PJ-supplemented mice exhibited significantly increased life spans compared to the water-fed mice.
In a study reported in 2006, researchers observed the effects of PJ on PSA values in prostate cancer patients who had rising PSA levels following treatment with surgery or radiation therapy. The study participants drank 8 ounces of PJ daily (570 mg/day total polyphenol gallic acid equivalents) for up to 33 months. Drinking PJ was associated with statistically significant increases in PSA doubling time. In addition, LNCaP cells were treated in vitro with the subjects' serum before and after the PJ intervention. Results of the in vitro experiments showed a decrease in cell growth and an increase in apoptosis following PJ treatment.
Current Clinical Trials
Check NCI's list of cancer clinical trials for CAM clinical trials on pomegranate-extract pill for prostate cancer, pomegranate juice for prostate cancer, and pomegranate liquid extract for prostate cancer that are actively enrolling patients.
General information about clinical trials is also available from the NCI Web site.
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.
|1.||Jurenka JS: Therapeutic applications of pomegranate (Punica granatum L.): a review. Altern Med Rev 13 (2): 128-44, 2008.|
|2.||Langley P: Why a pomegranate? BMJ 321 (7269): 1153-4, 2000.|
|3.||Viuda-Martos M, Fernandez-Lopez J, Perez-Alvarez JA: Pomegranate and its many functional components as related to human health: a review. Compr Rev Food Sci Food Saf 9 (6): 635-54, 2010. Available online. Last accessed February 2, 2012.|
|4.||Basu A, Penugonda K: Pomegranate juice: a heart-healthy fruit juice. Nutr Rev 67 (1): 49-56, 2009.|
|5.||Aviram M, Rosenblat M, Gaitini D, et al.: Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr 23 (3): 423-33, 2004.|
|6.||Menezes SM, Cordeiro LN, Viana GS: Punica granatum (pomegranate) extract is active against dental plaque. J Herb Pharmacother 6 (2): 79-92, 2006.|
|7.||Seeram NP, Aronson WJ, Zhang Y, et al.: Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland. J Agric Food Chem 55 (19): 7732-7, 2007.|
|8.||Albrecht M, Jiang W, Kumi-Diaka J, et al.: Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. J Med Food 7 (3): 274-83, 2004.|
|9.||Gasmi J, Sanderson JT: Growth Inhibitory, Antiandrogenic, and Pro-apoptotic Effects of Punicic Acid in LNCaP Human Prostate Cancer Cells. J Agric Food Chem : , 2010.|
|10.||Hong MY, Seeram NP, Heber D: Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor. J Nutr Biochem 19 (12): 848-55, 2008.|
|11.||Lansky EP, Jiang W, Mo H, et al.: Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Invest New Drugs 23 (1): 11-20, 2005.|
|12.||Koyama S, Cobb LJ, Mehta HH, et al.: Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF-IGFBP axis. Growth Horm IGF Res 20 (1): 55-62, 2010.|
|13.||Malik A, Afaq F, Sarfaraz S, et al.: Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci U S A 102 (41): 14813-8, 2005.|
|14.||Kasimsetty SG, Bialonska D, Reddy MK, et al.: Effects of pomegranate chemical constituents/intestinal microbial metabolites on CYP1B1 in 22Rv1 prostate cancer cells. J Agric Food Chem 57 (22): 10636-44, 2009.|
|15.||Wang L, Alcon A, Yuan H, et al.: Cellular and molecular mechanisms of pomegranate juice-induced anti-metastatic effect on prostate cancer cells. Integr Biol (Camb) 3 (7): 742-54, 2011.|
|16.||Sartippour MR, Seeram NP, Rao JY, et al.: Ellagitannin-rich pomegranate extract inhibits angiogenesis in prostate cancer in vitro and in vivo. Int J Oncol 32 (2): 475-80, 2008.|
|17.||Adhami VM, Siddiqui IA, Syed DN, et al.: Oral infusion of pomegranate fruit extract inhibits prostate carcinogenesis in the TRAMP model. Carcinogenesis 33 (3): 644-51, 2012.|
|18.||Pantuck AJ, Leppert JT, Zomorodian N, et al.: Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res 12 (13): 4018-26, 2006.|
|19.||Forest CP, Padma-Nathan H, Liker HR: Efficacy and safety of pomegranate juice on improvement of erectile dysfunction in male patients with mild to moderate erectile dysfunction: a randomized, placebo-controlled, double-blind, crossover study. Int J Impot Res 19 (6): 564-7, 2007 Nov-Dec.|
This section contains the following key information:
General Information & History
Although records of soy use in China date back to the eleventh century BC, it was not until the 18th century that the plant reached Europe and the United States. The soybean is an incredibly versatile plant: it can be processed into a variety of products including soy milk, miso, tofu, soy flour, and soy oil.
Soy foods contain a number of phytochemicals that may have health benefits but isoflavones have garnered the most attention. Among the isoflavones found in soybeans, genistein is the most abundant and may have the most biological activity. Other isoflavones found in soy include daidzein and glycitein. Isoflavones help soybeans survive in times of stress and have antioxidant , antimicrobial , and antifungal properties.
Isoflavones are quickly taken up by the gut and can be detected in plasma as soon as 30 minutes after the consumption of soy products. Studies suggest that maximum levels of isoflavone plasma concentration may be achieved by 6 hours following soy product consumption. Isoflavones are phytoestrogens (they bind to estrogen receptors ) with a greater binding affinity for estrogen receptor beta than for estrogen receptor alpha.
Some studies suggest that soy may have health benefits, including decreasing risk for cardiovascular disease and cancer . A link between isoflavones and cancer was discovered in 1987 when it was shown that genistein inhibited a protein tyrosine kinase that is often overexpressed in cancer cells. Subsequently, genistein was found to inhibit multiple protein tyrosine kinases relevant to cancer cell proliferation. In addition, numerous studies have shown that prostate cancer incidence is very low in Asian countries, where diets tend to be high in soy.
In vitro studies
A number of laboratory studies have examined ways in which soy components affect prostate cancer cells. In one study, human prostate cancer cells and normal prostate epithelial cells were treated with either an ethanol vehicle (carrier) or isoflavones. Treatment with genistein decreased COX-2 mRNA and protein levels in cancer cells and normal epithelial cells more than did treatment with the vehicle. In addition, cells treated with genistein exhibited reduced secretion of prostaglandin E2 (PGE2) and reduced mRNA levels of the prostaglandin receptors EP4 and FP, suggesting that genistein may exert chemopreventive effects by inhibiting the synthesis of prostaglandins, which promote inflammation . In another study, human prostate cancer cells were treated with genistein or daidzein. The isoflavones were shown to down-regulate growth factors involved in angiogenesis (e.g., EGF and insulin-like growth factor 1 [IGF1]) and the interleukin -8 gene , which is associated with cancer progression. These findings suggest that genistein and daidzein may have chemopreventive properties.
Combinations of isoflavones
Some experiments have been conducted comparing effects of individual isoflavones with isoflavone combinations on prostate cancer cells. In one such study, human prostate cancer cells were treated with a soy extract (containing genistin, daidzin, and glycitin), genistein, or daidzein. The soy extract induced cell cycle arrest and apoptosis in prostate cancer cells to a greater degree than did treatment with the individual isoflavones. Genistein and daidzein activated apoptosis in noncancerousbenign prostatic hyperplasia (BPH) cells, but the soy extract had no effect on those cells. These findings suggest that products containing a combination of active compounds (e.g., "whole foods") may be more effective in preventing cancer than individual compounds. Similarly, in another study, prostate cancer cells were treated with genistein, biochanin A, quercetin, doublets of those compounds (e.g., genistein + quercetin), or with all three compounds. All of the treatments resulted in decreased cell proliferation, but the greatest reductions occurred using the combination of genistein, biochanin A, and quercetin. The triple combination treatment induced more apoptosis in prostate cancer cells than did individual or doublet compound treatments. These results indicate that combining phytoestrogens may increase the effectiveness of the individual compounds.
At least one study has examined the combined effect of soy isoflavones and curcumin . Human prostate cancer cells were treated with isoflavones, curcumin, or a combination of the two. Curcumin and isoflavones in combination were more effective in lowering PSA levels and expression of the androgen receptor than were curcumin or the isoflavones individually.
Animal models of prostate cancer have been used in studies investigating the effects of soy and isoflavones on the disease. Wild-type and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control diets or diets containing genistein (250 mg genistein/kg chow). The TRAMP mice fed with genistein exhibited reduced cell proliferation in the prostate compared to TRAMP mice fed a control diet. The genistein-supplemented diet also reduced levels of ERK-1 and ERK-2 (proteins important in stimulating cell proliferation) as well as the growth factor receptors EGFR and IGF-1R in TRAMP mice, suggesting that down regulation of these proteins may be one mechanism by which genistein exerts chemopreventive effects. In another study, following the appearance of spontaneous prostatic intraepithelial neoplasia lesions , TRAMP mice were fed control diets or diets supplemented with genistein (250 or 1000 mg genistein/kg chow). Mice fed low-dose genistein exhibited more cancer cell metastasis and greater osteopontin expression than mice fed the control or the high-dose genistein diet. These results indicate that timing and dose of genistein treatment may affect prostate cancer outcomes and that genistein may exert biphasic control over prostate cancer. In a study reported in 2008, athymic mice were implanted with human prostate cancer cells and fed a control or genistein-supplemented diet (100 or 250 mg genistein/kg chow). Mice that were fed genistein exhibited less cancer cell metastasis, but no change in primary tumor volume, than did mice fed a control diet. Furthermore, other data suggested that genistein inhibits metastasis by impairing cancer cell detachment. In contrast, in a study reported in 2011, there were more metastases in secondary organs in genistein-treated mice than in vehicle-treated mice. In this latter study, mice were implanted with human prostate cancer xenografts and treated daily with genistein dissolved in peanut oil (80 mg genistein/kg body weight/day or 400 mg genistein/kg body weight/day) or peanut oil vehicle by gavage. In addition, there was a reduction in tumor cell apoptosis in the genistein-treated mice compared with the vehicle-treated mice. These findings suggest that genistein may stimulate metastasis in 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/day), mixed isoflavones (50 mg/kg body weight/day; contained 43% genistein, 21% daidzein, and 2% glycitein) and/or radiation. Mixed isoflavones were more effective than genistein in inhibiting prostate tumor growth, and combining isoflavones with radiation resulted in the largest inhibition of tumor growth. In addition, mice given soy isoflavones in combination with radiation did not exhibit lymph node metastasis, which was seen previously in other experiments combining genistein with radiation. These findings suggest that mixed isoflavones may increase the efficacy of radiation therapy for prostate cancer.
Numerous clinical studies have been conducted examining the impact of soy use on indicators of the effectiveness of prostate cancer prevention or treatment approaches. These studies have included a wide range of participants (from healthy control subjects to prostate cancer patients at various stages of the disease) and have used a number of different interventions such as soy supplements, beverages, and breads.
In 2009, a meta-analysis of studies that investigated soy food consumption and risk of prostate cancer was reported. The results of this meta-analysis suggested that high consumption of nonfermented soy foods (e.g., tofu and soybean milk) may significantly decrease the risk of prostate cancer. No association was found between high consumption of fermented soy foods (e.g., miso) and prostate cancer risk. In another study, urinary concentrations of phytoestrogens were assessed in healthy Jamaican men and men newly diagnosed with prostate cancer. There were no differences in urinary concentrations of the isoflavones genistein and daidzein between healthy men and prostate cancer patients. Men who produced equol (a metabolite of daidzein) were at a lower risk of prostate cancer than men who were non-producers.
In one study, Japanese men who had undergone prostate biopsy , but who did not have cancer, were randomly assigned to receive a supplement containing soy isoflavones (40 mg; comprised of 66% daidzein, 24% glycitin, and 10% genistin) and curcumin (100 mg) or a placebo for 6 months. Overall, there were no differences in PSA levels between the placebo and the treatment groups. However, when subjects were subdivided according to baseline PSA level, patients with a higher baseline PSA level (PSA ≥10 ng/mL) who received supplements exhibited statistically significantly larger decreases in PSA than did patients in the placebo group (P = .02).
Although soy is a standard part of many Asian diets, it is less common in Western diets. Therefore, feasibility studies were undertaken to investigate whether Western participants would adhere to soy-supplementation interventions. In one study, healthy men were randomly assigned to consume a high-soy (two daily soy servings) or low-soy (usual diet) diet for 3 months. Following a 1-month washout period, the men crossed over to the other treatment. Reductions approaching statistical significance were seen in PSA levels following the high-soy diet. These findings suggest that this type of soy intervention study is feasible (i.e., the participants complied with dietary instructions) and that soy may be a potential chemopreventive agent.
In another study, men at risk for prostate cancer or with low-grade prostate cancer received one of three types of protein isolate (soy protein, alcohol-washed soy protein [a common method of producing soy protein concentrate, but results in some loss of isoflavones], or milk protein) for 6 months. The isoflavone content of the interventions was 107±5.0 mg/day for soy protein isolate (containing 53% genistein, 35% daidzein, and 11% glycitein), <6±0.7 mg/day for alcohol-washed soy protein (containing 57% genistein, 20% daidzein, and 23% glycitein), and 0 mg/day for milk protein. Soy protein consumption did not alter prostate tissue biomarkers, alcohol-washed soy protein exerted mixed effects, and less prostate cancer was detected after 6 months in men who had consumed soy proteins compared with men who consumed milk protein.
Other plants also contain some of the same isoflavones found in soy. In one study, patients with elevated PSA levels but negative prostate biopsy specimens received a daily isoflavone preparation extracted from red clover (60 mg/day; contained the isoflavones genistein, daidzein, formononetin, and biochanin A) and were followed up for 1 year. Following 12 months of treatment, there was a significant reduction in PSA levels (P = .019) and a nonsignificant decrease in prostate volume (P = .097). In addition, the isoflavone intervention was well tolerated by the patients and did not cause side effects.
Treatment of prostate cancer
In a study reported in 2010, patients with rising PSA levels who had been treated with radiation as the primary treatment for prostate cancer drank a soy beverage daily (providing approximately 65-90 mg isoflavones) for 6 months. The results showed that the soy beverage was well-tolerated in North American men and was associated with an increase in PSA doubling time. These findings suggested that drinking the soy beverage may have helped to slow the progression of prostate cancer.
In one small (n = 20), open-label study, patients with rising PSA levels following previous therapy consumed soy milk three times a day (141 mg isoflavonoid/day) for 12 months. The results showed that drinking soy milk was associated with a greater than 50% decline in PSA level in one patient and decreases in the rate of rise in serum PSA in 14 patients.
In another study, prostate cancer patients received genistein-rich supplements (450 mg genistein/day, plus 450 mg other aglycone isoflavones/day) for 6 months. The majority of patients who were undergoing active surveillance exhibited either no rise in PSA level or a decline of less than 50%. In a similar study, prostate cancer patients undergoing active surveillance were randomly assigned to receive a placebo or an isoflavone supplement containing high doses of genistein and daidzein (450 mg genistein, 300 mg daidzein, and other isoflavones) for 6 months. Then, for an additional 6 months, all participants received the isoflavone supplement. Although treatment with the supplements raised serum concentration levels of genistein and daidzein, there was no effect on PSA levels.
In a study reported in 2011, prostate cancer patients scheduled for radical prostatectomy were randomly assigned to receive a placebo or 30 mg genistein daily for 3 to 6 weeks before surgery. Among the patients who received genistein, serum PSA levels decreased by 7.8%, whereas serum PSA levels increased by 4.4% in patients who received the placebo; this difference approached statistical significance (P = .051). In addition, the genistein intervention resulted in significantly lower levels of total cholesterol compared to placebo treatment (P = .013).
In one study, early-stage prostate cancer patients were randomly assigned to receive a soy protein supplement (60 mg/day isoflavones) or a placebo daily for 12 weeks. Patients who received the soy protein supplement exhibited larger decreases in total serum PSA and free testosterone than did patients who received the placebo, but these differences were not statistically significant. These findings suggest that soy protein may have potential to slow down progression of prostate cancer.
Whole soy products
Clinical studies have been conducted in prostate cancer patients to test soy as a possible treatment for prostate cancer. In one study, prostate cancer patients scheduled to undergo radical prostatectomy were randomly assigned to receive soy supplements (three 27.2 mg tablets/day; each tablet contained 10.6 mg genistein, 13.3 mg daidzein, and 3.2 mg glycitein) or a placebo for 2 weeks before surgery. The isoflavone concentration in prostatic tissue was six-fold higher than in serum following treatment with the soy supplements, suggesting that the prostate may accumulate potentially anticarcinogenic levels of isoflavones. In another study, prostate cancer patients scheduled for radical prostatectomy were instructed to eat bread containing high levels of phytoestrogens (soy or soy + linseed; 117 mg/day isoflavones) or low levels of phytoestrogens (wheat bread) until surgery. Patients who ate the high-phytoestrogen bread saw more favorable changes in PSA levels than did patients who ate the wheat bread, indicating that diets rich in phytoestrogens may help to reduce risk of prostate cancer development and progression.
In another small study, ten men with prostate cancer recurrence were advised to consume three 8-ounce glasses of soy milk every day for 2 years. Clinical benefits (i.e., decreased, attenuated, or stabilized PSA) were observed in five of the ten participants, suggesting that soy products may have positive effects in some prostate cancer patients.
Management of hormone therapy side-effects
Androgen deprivation therapy is commonly used for locally advanced and metastatic prostate cancer. However, this treatment is associated with a number of adverse side effects including sexual dysfunction, decreased quality of life , and changes in cognition. In one study, men undergoing androgen deprivation therapy were randomly assigned to receive a placebo or an isoflavone supplement (soy protein powder mixed with beverages; 160 mg/day isoflavones) for 12 weeks. The study results showed no improvement in side effects following isoflavone treatment compared with placebo treatment.
Effects on inflammatory parameters
In another study of men undergoing androgen deprivation therapy, participants were randomly assigned to receive high-dose isoflavone supplements (providing 160 mg/day total isoflavones and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein) or a placebo for 12 weeks. The results showed no difference between the two groups in PSA levels or in levels of metabolic and inflammatory parameters (e.g., glucose , interleukin-6).
Prostaglandins promote inflammation and may contribute to cancer by increasing cell proliferation and inhibiting apoptosis. The findings of a study reported in 2009 suggest that soy isoflavones may have chemopreventive effects via inhibition of the prostaglandin pathway. In the study, prostate cancer patients scheduled to undergo prostatectomy were randomly assigned to receive a placebo or a soy isoflavone supplement (providing 81.6 mg/day isoflavones) for at least 2 weeks before surgery. The results showed a significant decrease in COX-2 mRNA levels (P < .01) and significant increases in p21 mRNA levels (P < .01) in prostatectomy specimens obtained from the soy-supplemented group compared with specimens from the placebo group.
Current Clinical Trials
Check NCI's list of cancer clinical trials for CAM clinical trials on soy isoflavones for prostate cancer and soy protein isolate for prostate cancer that are actively enrolling patients.
General information about clinical trials is also available from the NCI Web site.
Overall, soy was well tolerated in clinical studies of prostate cancer patients.[22,24,26,28,31,34] The most commonly reported side effects were gastrointestinal symptoms.[25,27,28] In addition, one study reported that a participant withdrew due to insomnia.
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