References

1. National Cancer Institute: SEER Stat Fact Sheets: Prostate. Bethesda, MD: National Cancer Institute, 2011. Available online. Last accessed February 11, 2016.
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. [PubMed: 21120540]
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. [PubMed: 20926547]
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. [PubMed: 15035882]
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. [PubMed: 14624907]
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. [PubMed: 18637112]
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 11 (2): 83-9, 2012. [PMC free article: PMC3213317] [PubMed: 21821653]
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. [PubMed: 14972473]
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. [PubMed: 18235127]
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. [PubMed: 15911931]
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. [PubMed: 14672107]

Overview

This section contains the following key information:

• Calcium is required for certain metabolic functions such as vascular contraction and vasodilation, muscle function, nerve transmission, intracellular signaling, and hormonal secretion.
• Major sources of calcium in the United States are food and dietary supplements.
• Studies of the association between calcium and prostate cancer have been limited to nutritional sources of calcium, such as dairy products.
• Some studies suggest that high total calcium intake may be associated with increased risk of advanced and metastatic prostate cancer, compared with lower intake of calcium.
• Additional research is needed to clarify the effects of calcium and/or dairy products on prostate cancer risk.

General Information and History

Calcium, the most abundant mineral in the body, is found in some foods, added to others, available as a dietary supplement, and present in some medicines (such as antacids). Calcium is required for vascular contraction and vasodilation, muscle function, nerve transmission, intracellular signaling, and hormonal secretion, although less than 1% of total body calcium is needed to support these critical metabolic functions.[1] Serum calcium is very tightly regulated and does not fluctuate with changes in dietary intake; the body uses bone tissue as a reservoir for, and source of calcium to maintain constant concentrations of calcium in blood, muscle, and intercellular fluids.[1]

The major sources of calcium in the U.S. population are food and dietary supplements.[2] According to recent National Health and Nutrition Examination Survey data, U.S. adults obtain 38% of their dietary calcium from milk and milk products, such as yogurt and cheese.[3] Nondairy sources include vegetables, such as Chinese cabbage, kale, and broccoli. Spinach provides calcium, but its bioavailability is poor. Most grains do not have high amounts of calcium unless they are fortified; however, they contribute calcium to the diet because they contain small amounts of calcium, and people consume them frequently. Foods fortified with calcium include many fruit juices and drinks, tofu, and cereals. In the United States, dietary supplements, including calcium supplements, are commonly used to prevent chronic diseases, including cancer.[1] Mean dietary calcium intakes for males aged 1 year and older ranged from 871 to 1,266 mg/day depending on life stage group (i.e., infant, adolescent, or adult). About 43% of the U.S. population uses dietary supplements containing calcium, which increases calcium intake by about 330 mg/day among supplement users.[1,2]

To evaluate the association between calcium intake and prostate cancer mortality and morbidity, it may be important to assess objective, biological markers of calcium, include data that account for nutritional and supplemental calcium intake, and control for other confounding factors. However, studies of association between calcium and prostate cancer have been limited to nutritional sources of calcium, such as dairy products. Although more than half of the U.S. population uses vitamin and mineral supplements (at an annual cost of over 11 billion dollars), few studies include supplement use in the association of disease risk, including prostate cancer or mortality rates.[1,2] (Refer to the PDQ summary on Prostate Cancer Prevention for more information.)

Preclinical/Animal Studies

Human Studies

References

1. Ross AC, Taylor CL, Yaktine AL, et al., eds.: Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press, 2011. Also available online. Last accessed April 19, 2016. [PubMed: 21796828]
2. Lampe JW: Dairy products and cancer. J Am Coll Nutr 30 (5 Suppl 1): 464S-70S, 2011. [PubMed: 22081693]
3. Fortmann SP, Burda BU, Senger CA, et al.: Vitamin, Mineral, and Multivitamin Supplements for the Primary Prevention of Cardiovascular Disease and Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality, 2013. Available online. Last accessed April 19, 2016. [PubMed: 24308073]
4. Tate PL, Bibb R, Larcom LL: Milk stimulates growth of prostate cancer cells in culture. Nutr Cancer 63 (8): 1361-6, 2011. [PubMed: 22043817]
5. Mordan-McCombs S, Brown T, Zinser G, et al.: Dietary calcium does not affect prostate tumor progression in LPB-Tag transgenic mice. J Steroid Biochem Mol Biol 103 (3-5): 747-51, 2007. [PMC free article: PMC1950667] [PubMed: 17307354]
6. Ray R, Banks M, Abuzahra H, et al.: Effect of dietary vitamin D and calcium on the growth of androgen-insensitive human prostate tumor in a murine model. Anticancer Res 32 (3): 727-31, 2012. [PMC free article: PMC4681513] [PubMed: 22399584]
7. Butler LM, Wong AS, Koh WP, et al.: Calcium intake increases risk of prostate cancer among Singapore Chinese. Cancer Res 70 (12): 4941-8, 2010. [PMC free article: PMC4219618] [PubMed: 20516117]
8. Kurahashi N, Inoue M, Iwasaki M, et al.: Dairy product, saturated fatty acid, and calcium intake and prostate cancer in a prospective cohort of Japanese men. Cancer Epidemiol Biomarkers Prev 17 (4): 930-7, 2008. [PubMed: 18398033]
9. Raimondi S, Mabrouk JB, Shatenstein B, et al.: Diet and prostate cancer risk with specific focus on dairy products and dietary calcium: a case-control study. Prostate 70 (10): 1054-65, 2010. [PubMed: 20232354]
10. Park Y, Mitrou PN, Kipnis V, et al.: Calcium, dairy foods, and risk of incident and fatal prostate cancer: the NIH-AARP Diet and Health Study. Am J Epidemiol 166 (11): 1270-9, 2007. [PubMed: 18000020]
11. Giovannucci E, Liu Y, Stampfer MJ, et al.: A prospective study of calcium intake and incident and fatal prostate cancer. Cancer Epidemiol Biomarkers Prev 15 (2): 203-10, 2006. [PubMed: 16492906]
12. Koh KA, Sesso HD, Paffenbarger RS Jr, et al.: Dairy products, calcium and prostate cancer risk. Br J Cancer 95 (11): 1582-5, 2006. [PMC free article: PMC2360740] [PubMed: 17106437]
13. Ahn J, Albanes D, Peters U, et al.: Dairy products, calcium intake, and risk of prostate cancer in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 16 (12): 2623-30, 2007. [PubMed: 18086766]
14. Park SY, Murphy SP, Wilkens LR, et al.: Calcium, vitamin D, and dairy product intake and prostate cancer risk: the Multiethnic Cohort Study. Am J Epidemiol 166 (11): 1259-69, 2007. [PubMed: 17925283]
15. Pettersson A, Kasperzyk JL, Kenfield SA, et al.: Milk and dairy consumption among men with prostate cancer and risk of metastases and prostate cancer death. Cancer Epidemiol Biomarkers Prev 21 (3): 428-36, 2012. [PMC free article: PMC3297731] [PubMed: 22315365]
16. Mitrou PN, Albanes D, Weinstein SJ, et al.: A prospective study of dietary calcium, dairy products and prostate cancer risk (Finland). Int J Cancer 120 (11): 2466-73, 2007. [PubMed: 17278090]
17. Kesse E, Bertrais S, Astorg P, et al.: Dairy products, calcium and phosphorus intake, and the risk of prostate cancer: results of the French prospective SU.VI.MAX (Supplémentation en Vitamines et Minéraux Antioxydants) study. Br J Nutr 95 (3): 539-45, 2006. [PubMed: 16512941]
18. Rohrmann S, Platz EA, Kavanaugh CJ, et al.: Meat and dairy consumption and subsequent risk of prostate cancer in a US cohort study. Cancer Causes Control 18 (1): 41-50, 2007. [PubMed: 17315319]
19. Baron JA, Beach M, Wallace K, et al.: Risk of prostate cancer in a randomized clinical trial of calcium supplementation. Cancer Epidemiol Biomarkers Prev 14 (3): 586-9, 2005. [PubMed: 15767334]
20. Gao X, LaValley MP, Tucker KL: Prospective studies of dairy product and calcium intakes and prostate cancer risk: a meta-analysis. J Natl Cancer Inst 97 (23): 1768-77, 2005. [PubMed: 16333032]
21. Huncharek M, Muscat J, Kupelnick B: Dairy products, dietary calcium and vitamin D intake as risk factors for prostate cancer: a meta-analysis of 26,769 cases from 45 observational studies. Nutr Cancer 60 (4): 421-41, 2008. [PubMed: 18584476]
22. Qin LQ, Xu JY, Wang PY, et al.: Milk consumption is a risk factor for prostate cancer in Western countries: evidence from cohort studies. Asia Pac J Clin Nutr 16 (3): 467-76, 2007. [PubMed: 17704029]
23. Bristow SM, Bolland MJ, MacLennan GS, et al.: Calcium supplements and cancer risk: a meta-analysis of randomised controlled trials. Br J Nutr 110 (8): 1384-93, 2013. [PubMed: 23601861]
24. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC: World Cancer Research Fund/American Institute for Cancer Research, 2007. Also available online. Last accessed January 7, 2016.
25. Aune D, Navarro Rosenblatt DA, Chan DS, et al.: Dairy products, calcium, and prostate cancer risk: a systematic review and meta-analysis of cohort studies. Am J Clin Nutr 101 (1): 87-117, 2015. [PubMed: 25527754]

Overview

This section contains the following key information:

• All tea originates from the Camellia sinensis (L.) Kuntze plant, and the methods by which the leaves are processed determine the type of tea produced. For green tea, the leaves are steamed and dried.
• Some research suggests that green tea may have a protective effect against cardiovascular disease and against various forms of cancer, including prostate cancer.
• Catechins are polyphenol compounds in tea that are associated with many of tea’s proposed health benefits.
• Epigallocatechin gallate (EGCG), the most abundant catechin in tea, acts as an androgen antagonist and can suppress prostate cancer cell proliferation, suppress production of prostate-specific antigen (PSA) by prostate cancer cells, and increase prostate cancer cell death in vitro.
• Oral intake of either a green tea catechin solution or EGCG alone was associated with reduced development of prostate cancer in studies with transgenic adenocarcinoma of the mouse prostate (TRAMP) mice.
• In Asian countries with a high per capita consumption of green tea, prostate cancer mortality rates are among the lowest in the world, and the risk of prostate cancer appears to be increased among Asian men who abandon their original dietary habits upon migrating to the United States. Case-control and cohort studies, so far, have variously shown beneficial or neutral results with the exception of one study that has shown an increased risk of the development of advanced prostate cancer with consumption of green tea.
• Results from a small placebo-controlled study of green tea catechins in men with high-grade prostatic intraepithelial neoplasia (HGPIN) showed a statistically significant decrease in the development of prostate cancer among men who were randomly assigned to receive the catechin supplement. A larger, multicenter, randomized trial is now under way.
• Studies of orally administered mixtures of tea catechins in men with prostate cancer have begun to provide information about biologic effects in this setting but are too preliminary to draw conclusions about clinical effectiveness.
• Green tea has been well tolerated in clinical studies of prostate cancer patients, with the most common side effects being mild gastrointestinal symptoms.

General Information and History

Sailors first brought tea to England in 1644, although tea has been popular in Asia since ancient times. After water, tea is the most consumed beverage in the world.[1] Tea originates from the C. sinensis plant, and the methods by which the leaves are processed determine the type of tea produced. Green tea is not fermented but is made by an enzyme deactivation step where intensive heat (i.e., roasting the freshly collected tea leaves in a wok or, historically, steaming the leaves) is applied to preserve the tea's polyphenols (catechins) and freshness. In contrast, the enzyme catalyzed polymerization and oxidation of catechins and other components produces darker colored black tea.[2] Oolong, a third major type of tea, contains polyphenols that are partially oxidized.[1]

The English word “tea” has its origins in China. Ch'a is the Mandarin word for “tea.” In the dialect spoken in the southern Chinese province of Fujian, the word for “tea” was pronounced “tay.” This term was borrowed by European traders who bought tea at the southern Chinese ports, and it evolved into tea (English), thé (French), and Tee (German). “Tea” is also used to describe infusions of medicinal herbs, such as sage and calamint.[3] In this PDQ information summary, “tea” refers to the leaves of the C. sinensis plant or the beverage brewed from those leaves.

Some observational and interventional studies suggest that green tea may have a protective effect against cardiovascular disease,[4] and there is evidence that green tea may protect against various forms of cancer.[5] Many of the health benefits associated with tea have been attributed to polyphenols.Catechins compose most of the polyphenols found in tea; of these, epigallocatechin-3-gallate (EGCG) has been the most widely researched.[6] Tea leaves also contain considerable amounts of oligomeric catechins, commonly known as oligomeric proanthocyanidins. Together with the catechin monomers, they constitute the green tea polyphenols (GTPs). GTP composition varies widely, depending on processing and source of the tea leaves.

Preclinical/Animal Studies

Human Studies

Adverse Effects

The safety of tea and tea compounds is supported by centuries of consumption by the human population. The bioavailability and tolerance to GTC at doses ranging from 600 to 1,000 mg of EGCG at single and multiple dosing schedule, and a duration of a few days to one year has been well documented in phase I/II clinical trials.[39-49] By conducting a phase I trial of oral green tea extract in adult patients with solid tumors, the authors reported that a safe dose of green tea extract was equivalent to seven to eight Japanese cups (120 mL) of green tea three times per day for 6 months.[50] The authors concluded that the side effects (neurological and gastrointestinal effects) of the green tea extract preparation were caffeine-related, and not from EGCG. In four phase I, single-dose and multidose studies that targeted healthy volunteers who took a botanical drug substance containing a mixture of catechins, Polyphenon E, and a dose range of 200 to 1,200 mg EGCG was well tolerated.[32,33,36-38,49,51] Adverse effects reported in these studies with a possible relationship to the study drug have been grade 2 to 3 and included asthenia, headache, abdominal pain, chest pain, diarrhea, dyspepsia, eructation, flatulence, nausea, vomiting, dizziness, vasodilation, and rash. These studies have demonstrated that although increased oral bioavailability occurs when GTCs are consumed in a fasting state, increased gastrointestinal toxicity is more common when EGCG is administered in a fasting state. Gastrointestinal adverse effects were usually mild, seen most often in the fasting condition, and at the higher dose level. 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.[41]

Green tea has been well tolerated in clinical studies of men with prostate cancer.[41,48] In a 2005 study, the most commonly reported side effects were gastrointestinal symptoms. These symptoms were mild for all but two men who experienced severe anorexia and moderate dyspnea.[43] With the duration of intervention in these studies ranging from single, one-time administration to a maximum of 90 days, the safety data from these studies are limited to short-term safety of EGCG and GTCs.

Data from clinical trials [36,38] report long-term safety (1 year) of EGCG containing GTCs, for use in men with precursor lesions of prostate cancer for prevention of prostate cancer. One study [36] administered approximately 300 mg EGCG per day for 1 year without any reported toxicities. However, the study had several limitations in that the agent stability and standardization were not subject to testing for catechin content throughout the duration of trial. Additionally, there were no objective measures or reports of compliance, agent-related toxicity, including liver toxicity monitoring and adherence-to-study agent.

In the recently completed U.S. trial, 400 mg of EGCG containing Polyphenon E was administered for 1 year to men with HGPIN and ASAP who were not fasting. The study was conducted under a U.S. Federal Drug Administration Investigational New Drug application, using a standardized agent that contained 400 mg of EGCG. Plasma levels of catechins, "adherence to study" agent, and agent-related toxicity—including liver toxicity—were monitored throughout the study. More possible and probable grade 2 through grade 3 events in men who received Polyphenon 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. Notably, all grade 1 through grade 2 toxicities in this trial were determined from monthly comprehensive metabolic panels, including liver function tests, and not from subject-reported symptoms.[38]

In recent years, oral consumption of varying doses and compositions of green tea extracts (GTEs) has been associated with several instances of hepatotoxicity.[27,47,52-54] Most affected patients were women, and many were consuming GTEs for the purpose of weight loss. Although hepatotoxicity in most cases resolved within 4 months of stopping GTE, there have been cases of positive rechallenge and liver failure requiring liver transplantation. One report described a case of acute liver failure that required transplantation in a woman who consumed green tea extract capsules.[53] The capsules contained Polyphenon 70A and 120 mg green tea extract. Because no other causal relationship could be identified, the treating physicians concluded that the fulminant liver failure experienced by this patient was most likely related to the consumption of over-the-counter GTE weight-loss supplements. In addition, the sale of an ethanolic GTE sold as a weight-reduction aid was suspended in 2003 after reports associated hepatotoxicity (four cases in Spain and nine cases in France) with its use.[54] Time to onset of hepatotoxicity following ingestion of GTEs ranged from several days to several months. Increased oral bioavailability occurs when GTEs are administered on an empty stomach after an overnight fast. Increased toxicity, including hepatotoxicity, is observed when Polyphenon E or EGCG is administered to fasted dogs.[27] Therefore, the U.S. Food and Drug Administration's Division of Drug Oncology Products has recommended that Polyphenon E be taken with food by subjects participating in clinical studies. In addition, subjects should have liver function tests performed while on treatment.

References

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7. Chuu CP, Chen RY, Kokontis JM, et al.: Suppression of androgen receptor signaling and prostate specific antigen expression by (-)-epigallocatechin-3-gallate in different progression stages of LNCaP prostate cancer cells. Cancer Lett 275 (1): 86-92, 2009. [PMC free article: PMC2980538] [PubMed: 18977589]
8. Thomas F, Holly JM, Persad R, et al.: Green tea extract (epigallocatechin-3-gallate) reduces efficacy of radiotherapy on prostate cancer cells. Urology 78 (2): 475.e15-21, 2011. [PubMed: 21676444]
9. Albrecht DS, Clubbs EA, Ferruzzi M, et al.: Epigallocatechin-3-gallate (EGCG) inhibits PC-3 prostate cancer cell proliferation via MEK-independent ERK1/2 activation. Chem Biol Interact 171 (1): 89-95, 2008. [PubMed: 17931610]
10. Luo KL, Luo JH, Yu YP: (-)-Epigallocatechin-3-gallate induces Du145 prostate cancer cell death via downregulation of inhibitor of DNA binding 2, a dominant negative helix-loop-helix protein. Cancer Sci 101 (3): 707-12, 2010. [PMC free article: PMC4040217] [PubMed: 20002680]
11. Rocha S, Generalov R, Pereira Mdo C, et al.: Epigallocatechin gallate-loaded polysaccharide nanoparticles for prostate cancer chemoprevention. Nanomedicine (Lond) 6 (1): 79-87, 2011. [PubMed: 21182420]
12. Sanna V, Pintus G, Roggio AM, et al.: Targeted biocompatible nanoparticles for the delivery of (-)-epigallocatechin 3-gallate to prostate cancer cells. J Med Chem 54 (5): 1321-32, 2011. [PubMed: 21306166]
13. Pandey M, Shukla S, Gupta S: Promoter demethylation and chromatin remodeling by green tea polyphenols leads to re-expression of GSTP1 in human prostate cancer cells. Int J Cancer 126 (11): 2520-33, 2010. [PMC free article: PMC2874465] [PubMed: 19856314]
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17. McCarthy S, Caporali A, Enkemann S, et al.: Green tea catechins suppress the DNA synthesis marker MCM7 in the TRAMP model of prostate cancer. Mol Oncol 1 (2): 196-204, 2007. [PMC free article: PMC2408886] [PubMed: 18521193]
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21. Teichert F, Verschoyle RD, Greaves P, et al.: Plasma metabolic profiling reveals age-dependency of systemic effects of green tea polyphenols in mice with and without prostate cancer. Mol Biosyst 6 (10): 1911-6, 2010. [PubMed: 20577699]
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23. Suttie A, Nyska A, Haseman JK, et al.: A grading scheme for the assessment of proliferative lesions of the mouse prostate in the TRAMP model. Toxicol Pathol 31 (1): 31-8, 2003 Jan-Feb. [PubMed: 12597447]
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32. Montague JA, Butler LM, Wu AH, et al.: Green and black tea intake in relation to prostate cancer risk among Singapore Chinese. Cancer Causes Control 23 (10): 1635-41, 2012. [PMC free article: PMC3695613] [PubMed: 22864870]
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35. Jian L, Xie LP, Lee AH, et al.: Protective effect of green tea against prostate cancer: a case-control study in southeast China. Int J Cancer 108 (1): 130-5, 2004. [PubMed: 14618627]
36. Bettuzzi S, Brausi M, Rizzi F, et al.: Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res 66 (2): 1234-40, 2006. [PubMed: 16424063]
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45. Chow HH, Cai Y, Alberts DS, et al.: Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E. Cancer Epidemiol Biomarkers Prev 10 (1): 53-8, 2001. [PubMed: 11205489]
46. Chow HH, Hakim IA, Vining DR, et al.: Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of Polyphenon E in healthy individuals. Clin Cancer Res 11 (12): 4627-33, 2005. [PubMed: 15958649]
47. Chow HH, Cai Y, Hakim IA, et al.: Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res 9 (9): 3312-9, 2003. [PubMed: 12960117]
48. Wang P, Aronson WJ, Huang M, et al.: Green tea polyphenols and metabolites in prostatectomy tissue: implications for cancer prevention. Cancer Prev Res (Phila) 3 (8): 985-93, 2010. [PMC free article: PMC3163459] [PubMed: 20628004]
49. Lee MJ, Maliakal P, Chen L, et al.: Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3-gallate by humans: formation of different metabolites and individual variability. Cancer Epidemiol Biomarkers Prev 11 (10 Pt 1): 1025-32, 2002. [PubMed: 12376503]
50. Pisters KM, Newman RA, Coldman B, et al.: Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol 19 (6): 1830-8, 2001. [PubMed: 11251015]
51. Yuan JM: Cancer prevention by green tea: evidence from epidemiologic studies. Am J Clin Nutr 98 (6 Suppl): 1676S-1681S, 2013. [PMC free article: PMC3831544] [PubMed: 24172305]
52. Bonkovsky HL: Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med 144 (1): 68-71, 2006. [PubMed: 16389263]
53. Molinari M, Watt KD, Kruszyna T, et al.: Acute liver failure induced by green tea extracts: case report and review of the literature. Liver Transpl 12 (12): 1892-5, 2006. [PubMed: 17133573]
54. Pedrós C, Cereza G, García N, et al.: [Liver toxicity of Camellia sinensis dried etanolic extract]. Med Clin (Barc) 121 (15): 598-9, 2003. [PubMed: 14622530]

Overview

This section contains the following key information:

• Lycopene is a carotenoid, a natural pigment made by plants and various fruits and vegetables, including tomatoes, apricots, guavas, and watermelon.
• Lycopene's absorption is improved with concurrent dietary fat intake.
• Lycopene inhibits androgen receptor expression in prostate cancer cells in vitro and, along with some of its metabolites, reduces prostate cancer cell proliferation and may modulate cell-cycle progression.
• Lycopene may also affect the insulin-like growth factor (IGF) intracellular pathway in prostate cancer cells.
• Results from several in vitro and animal studies have indicated that lycopene may have chemopreventive effects for cancers of the prostate, skin, breast, lung, and liver; however, human trials have been inconsistent in their findings.
• Clinical trials utilizing lycopene in prostate cancer patients with various different clinical presentations (e.g., early stage, prostate-specific antigen (PSA) relapse, advanced disease) have yielded inconsistent results.
• The U.S. Food and Drug Administration (FDA) has accepted the determination by various companies that their lycopene-containing products meet the FDA’s requirements for the designation of Generally Recognized as Safe (GRAS). In clinical trials involving prostate cancer patients, doses ranging from 10 to 120 mg/d have been well tolerated, with only occasional mild-to-moderate gastrointestinal toxicities.

General Information and History

Lycopene is a carotenoid, a natural pigment made by plants, which helps to protect plants from light-induced stress,[1] and it also transfers light energy during photosynthesis.[2] Lycopene is found in a number of fruits and vegetables, including apricots, guavas, and watermelon, but the majority of lycopene consumed in the United States is from tomato-based products.[1] The bioavailability of lycopene is greater in processed tomato products, such as tomato paste and tomato puree, than it is in raw tomatoes.[3] When ingested, lycopene is broken down into a number of metabolites and is thought to have various biological functions, including antioxidant capabilities and a role in gap-junction communication.[4]

There is evidence that dietary fat may help increase the absorption of carotenoids, including lycopene. In one experiment, healthy volunteers consumed mixed-vegetable salads with nonfat, low-fat, or full-fat salad dressing. Analysis of blood samples indicated that eating full-fat salad dressing led to more carotenoid absorption than eating low-fat or nonfat dressing.[5] Results of a randomized study published in 2005 revealed that cooking diced tomatoes with olive oil significantly increased lycopene absorption compared with cooking tomatoes without olive oil.[6] According to one study,[7] there was no difference in plasma lycopene levels following consumption of tomatoes mixed with olive oil or tomatoes mixed with sunflower oil, suggesting that absorption of lycopene may not be dependent on the type of oil used. However, this same study found that combining olive oil, but not sunflower oil, with tomatoes resulted in greater plasma antioxidant activity.

Lycopene has been investigated for its role in chronic diseases, including cardiovascular disease and cancer. Numerous epidemiological studies suggest that lycopene may help prevent cardiovascular disease, although some interventional studies have shown mixed results.[3] Lycopene may protect against cardiovascular disease by decreasing cholesterol synthesis and increasing the degradation of low-density lipoproteins.[8] A number of in vitro and in vivo studies suggest that lycopene may also be protective against cancers of the skin, breast, lung, and liver.[9] However, epidemiological studies reported to date have yielded inconsistent findings regarding lycopene's potential in reducing cancer risk. The few human intervention trials have been small and generally focused on intermediate endpoints and thus have not been definitive.[2,10]

In 2004, the FDA received two petitions for qualified health claims regarding tomatoes, lycopene, and reduced cancer risk. In a 2007 review, the FDA concluded there was not enough evidence to support a claim that lycopene helps reduce cancer risk. The FDA found there was no evidence of a link between tomato consumption and lung, colorectal, breast, cervical, or endometrial cancers, and there was limited evidence for an association between tomato consumption and reduced risks of prostate, ovarian, gastric, and pancreatic cancers.[11]

Preclinical/Animal Studies

Human Studies

Adverse Effects

Lycopene has been well tolerated in a number of clinical trials involving prostate cancer patients.[31,33,34,36,39] When adverse effects occurred, they tended to present as gastrointestinal symptoms[41] and, in one study, the symptoms resolved when lycopene was taken with meals.[40] Another study reported that one participant withdrew because of diarrhea.[38]

The 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).[43]

References

1. Kopec R, Schwartz SJ, Hadley C: Lycopene. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 504-17.
2. van Breemen RB, Pajkovic N: Multitargeted therapy of cancer by lycopene. Cancer Lett 269 (2): 339-51, 2008. [PMC free article: PMC2615641] [PubMed: 18585855]
3. Mordente A, Guantario B, Meucci E, et al.: Lycopene and cardiovascular diseases: an update. Curr Med Chem 18 (8): 1146-63, 2011. [PubMed: 21291369]
4. Mein JR, Lian F, Wang XD: Biological activity of lycopene metabolites: implications for cancer prevention. Nutr Rev 66 (12): 667-83, 2008. [PMC free article: PMC6824483] [PubMed: 19019036]
5. Brown MJ, Ferruzzi MG, Nguyen ML, et al.: Carotenoid bioavailability is higher from salads ingested with full-fat than with fat-reduced salad dressings as measured with electrochemical detection. Am J Clin Nutr 80 (2): 396-403, 2004. [PubMed: 15277161]
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. [PubMed: 15927929]
7. Lee A, Thurnham DI, Chopra M: Consumption of tomato products with olive oil but not sunflower oil increases the antioxidant activity of plasma. Free Radic Biol Med 29 (10): 1051-5, 2000. [PubMed: 11084294]
8. Arab L, Steck S: Lycopene and cardiovascular disease. Am J Clin Nutr 71 (6 Suppl): 1691S-5S; discussion 1696S-7S, 2000. [PubMed: 10837319]
9. Khan N, Afaq F, Mukhtar H: Cancer chemoprevention through dietary antioxidants: progress and promise. Antioxid Redox Signal 10 (3): 475-510, 2008. [PubMed: 18154485]
10. Ilic D, Forbes KM, Hassed C: Lycopene for the prevention of prostate cancer. Cochrane Database Syst Rev (11): CD008007, 2011. [PMC free article: PMC8939370] [PubMed: 22071840]
11. Kavanaugh CJ, Trumbo PR, Ellwood KC: The U.S. Food and Drug Administration's evidence-based review for qualified health claims: tomatoes, lycopene, and cancer. J Natl Cancer Inst 99 (14): 1074-85, 2007. [PubMed: 17623802]
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. [PubMed: 14608044]
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. [PubMed: 21207319]
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. [PubMed: 20699249]
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. [PubMed: 21334870]
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. [PubMed: 20819671]
17. Qiu X, Yuan Y, Vaishnav A, et al.: Effects of lycopene on protein expression in human primary prostatic epithelial cells. Cancer Prev Res (Phila) 6 (5): 419-27, 2013. [PMC free article: PMC3644332] [PubMed: 23483004]
18. 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. [PMC free article: PMC3033590] [PubMed: 21403837]
19. Konijeti R, Henning S, Moro A, et al.: Chemoprevention of prostate cancer with lycopene in the TRAMP model. Prostate 70 (14): 1547-54, 2010. [PMC free article: PMC2930120] [PubMed: 20687227]
20. Mossine VV, Chopra P, Mawhinney TP: Interaction of tomato lycopene and ketosamine against rat prostate tumorigenesis. Cancer Res 68 (11): 4384-91, 2008. [PubMed: 18519700]
21. 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. [PubMed: 21462328]
22. Yang CM, Lu YL, Chen HY, et al.: Lycopene and the LXRα agonist T0901317 synergistically inhibit the proliferation of androgen-independent prostate cancer cells via the PPARγ-LXRα-ABCA1 pathway. J Nutr Biochem 23 (9): 1155-62, 2012. [PubMed: 22137263]
23. Mariani S, Lionetto L, Cavallari M, et al.: Low prostate concentration of lycopene is associated with development of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia. Int J Mol Sci 15 (1): 1433-40, 2014. [PMC free article: PMC3907878] [PubMed: 24451130]
24. 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. [PMC free article: PMC3070045] [PubMed: 21335507]
25. 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. [PubMed: 19443241]
26. 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. [PubMed: 15006906]
27. Chen J, Song Y, Zhang L: Lycopene/tomato consumption and the risk of prostate cancer: a systematic review and meta-analysis of prospective studies. J Nutr Sci Vitaminol (Tokyo) 59 (3): 213-23, 2013. [PubMed: 23883692]
28. 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. [PubMed: 16434593]
29. Peters U, Leitzmann MF, Chatterjee N, et al.: Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 16 (5): 962-8, 2007. [PubMed: 17507623]
30. Zu K, Mucci L, Rosner BA, et al.: Dietary lycopene, angiogenesis, and prostate cancer: a prospective study in the prostate-specific antigen era. J Natl Cancer Inst 106 (2): djt430, 2014. [PMC free article: PMC3952200] [PubMed: 24463248]
31. Talvas J, Caris-Veyrat C, Guy L, et al.: Differential effects of lycopene consumed in tomato paste and lycopene in the form of a purified extract on target genes of cancer prostatic cells. Am J Clin Nutr 91 (6): 1716-24, 2010. [PubMed: 20392890]
32. Kim HS, Bowen P, Chen L, et al.: Effects of tomato sauce consumption on apoptotic cell death in prostate benign hyperplasia and carcinoma. Nutr Cancer 47 (1): 40-7, 2003. [PubMed: 14769536]
33. 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. [PubMed: 16301113]
34. Bunker CH, McDonald AC, Evans RW, et al.: A randomized trial of lycopene supplementation in Tobago men with high prostate cancer risk. Nutr Cancer 57 (2): 130-7, 2007. [PubMed: 17571945]
35. Kucuk O, Sarkar FH, Djuric Z, et al.: Effects of lycopene supplementation in patients with localized prostate cancer. Exp Biol Med (Maywood) 227 (10): 881-5, 2002. [PubMed: 12424329]
36. Barber NJ, Zhang X, Zhu G, et al.: Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study. Prostate Cancer Prostatic Dis 9 (4): 407-13, 2006. [PubMed: 16983396]
37. Kumar NB, Besterman-Dahan K, Kang L, et al.: Results of a Randomized Clinical Trial of the Action of Several Doses of Lycopene in Localized Prostate Cancer: Administration Prior to Radical Prostatectomy. Clin Med Urol 1: 1-14, 2008. [PMC free article: PMC2846655] [PubMed: 20354574]
38. 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. [PubMed: 16765186]
39. Ansari MS, Gupta NP: Lycopene: a novel drug therapy in hormone refractory metastatic prostate cancer. Urol Oncol 22 (5): 415-20, 2004 Sep-Oct. [PubMed: 15464923]
40. Schwenke C, Ubrig B, Thürmann P, et al.: Lycopene for advanced hormone refractory prostate cancer: a prospective, open phase II pilot study. J Urol 181 (3): 1098-103, 2009. [PubMed: 19150092]
41. Jatoi A, Burch P, Hillman D, et al.: A tomato-based, lycopene-containing intervention for androgen-independent prostate cancer: results of a Phase II study from the North Central Cancer Treatment Group. Urology 69 (2): 289-94, 2007. [PubMed: 17320666]
42. Magbanua MJ, Roy R, Sosa EV, et al.: Gene expression and biological pathways in tissue of men with prostate cancer in a randomized clinical trial of lycopene and fish oil supplementation. PLoS One 6 (9): e24004, 2011. [PMC free article: PMC3164676] [PubMed: 21912659]
43. Generally Recognized as Safe (GRAS) Notice Inventory. Silver Spring, Md: Food and Drug Administration, 2011. Available online. Last accessed April 19, 2016.

Overview

This section contains the following key information:

• Citrus pectin is a complex polysaccharide found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature.
• Preclinical research suggests that modified citrus pectin (MCP) may have effects on cancer growth and metastasis through multiple potential mechanisms.
• Very limited clinical research has been done with a couple of citrus pectin-containing products. For prostate cancer patients, the results suggest some potential clinical benefits with relatively minor and infrequent adverse events.

General Information and History

Pectin is a complex polysaccharide contained in the primary cell walls of terrestrial plants. The word ‘pectin’ comes from the Greek word for congealed or curdled. Plant pectin is used in food processing as a gelling agent and also in the formulation of oral and topical medicines as a stabilizer and nonbiodegradable matrix to support controlled drug delivery.[1] Citrus pectin is found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature.[2] Modification results in shorter molecules that dissolve better in water and are more readily absorbed by the body than are complex, longer chain citrus pectins.[3] One of the molecular targets of MCP is galectin-3, a protein found on the surface and within mammalian cells that is involved in many cellular processes, including cell adhesion, cell activation and chemoattraction, cell growth and differentiation, the cell cycle, and apoptosis; MCP inhibits galectin-3 activity.[2]

Some research suggests that MCP may be protective against various types of cancer, including colon, lung, and prostate cancer. MCP may exert its anticancer effects by interfering with tumor cell metastasis or by inducing apoptosis.[4]

MCP was also shown to activate natural killer cells in leukemic cell cultures, suggesting it may be able to stimulate the immune system.[5]

Preclinical Studies/Animal Studies

Human Studies

Adverse Effects

In one prospective pilot study, MCP was well tolerated by the majority of treated patients, with the most commonly reported side effects being pruritus, dyspepsia, and flatulence.[3] In another study, no serious side effects from MCP were reported, although three patients withdrew from the study due to abdominal cramps and diarrhea that improved once treatment was halted.[10]

References

1. Mohnen D: Pectin structure and biosynthesis. Curr Opin Plant Biol 11 (3): 266-77, 2008. [PubMed: 18486536]
2. Glinsky VV, Raz A: Modified citrus pectin anti-metastatic properties: one bullet, multiple targets. Carbohydr Res 344 (14): 1788-91, 2009. [PMC free article: PMC2782490] [PubMed: 19061992]
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 April 19, 2016.
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. [PubMed: 17513886]
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. [PMC free article: PMC3161912] [PubMed: 21816083]
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. [PubMed: 20462856]
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. [PMC free article: PMC3032324] [PubMed: 21368866]
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. [PubMed: 11134977]
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. [PubMed: 7853416]
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. [PubMed: 14663471]

Overview

This section contains the following key information:

• The pomegranate (Punica granatum L.) is native to Asia and cultivated widely throughout world.
• Various components of the pomegranate fruit contain bioactive compounds, including catechin phenolics, related flavonoids, and anthocyanins, some of which have antioxidant activity.
• Pomegranate juice and extract, as well as some of their bioactive components, inhibit the proliferation of various prostate cancer cell lines in vitro and induce apoptotic cell death in a dose-dependent manner.
• Cytochrome P450 enzyme inhibition and effects on insulin-like growth factor binding protein-3 (IGFBP-3) have been identified as being involved in the in vitro anticancer activity.
• Studies in rodent models of prostate cancer have shown that ingestion of pomegranate juice can decrease the rate of development, growth, and spread of prostate cancer.
• The only fully reported clinical trial of the use of pomegranate juice in men with prostate cancer showed that, on average, study participants who drank the juice had an increase in their prostate-specific antigen (PSA) doubling time (PSADT).
• No serious adverse effects have been reported in clinical trials of pomegranate juice administration (8 oz per day for up to 33 months).
• A phase II study reported that pomegranate extract was associated with an increase of at least 6 month in PSADT in both treatment arms (different doses), without adverse effects. However, a phase III placebo-controlled trial of pomegranate juice and extract did not show a significant increase in PSADT.

General Information and History

The pomegranate (Punica granatum L.) is a member of the Punicaceae family native to Asia (from Iran to northern India) and cultivated throughout the Mediterranean, Southeast Asia, East Indies, Africa, and the United States.[1] The history of the pomegranate goes back centuries—the fruit is considered sacred by many religions and has been used for medicinal purposes since ancient times.[2] The fruit is comprised of peel (pericarp), seeds, and aril (outer layer surrounding the seeds). The peel makes up 50% of the fruit and contains a number of bioactive compounds, including phenolics, flavonoids, and ellagitannins, and minerals such as potassium, magnesium, and sodium. Arils are mainly composed of water and also contain phenolics and flavonoids. Anthocyanins, which are flavonoid present in arils, are responsible for the fruit's and its juice’s red color.[3] The majority of antioxidant activity comes from ellagitannins.[4]

Research studies suggest that pomegranates have beneficial effects on a number of health conditions, including cardiovascular disease,[5] and may also have positive effects on oral or dental health.[6]

Preclinical Studies/Animal Studies

Human Studies

In a study reported in 2006, researchers observed the effects of PJ on PSA values in prostate cancer patients (N = 48) who had rising PSA levels following treatment with surgery or radiation therapy. The study participants drank 8 ounces of PJ daily (570 mg/day total polyphenol gallic acid equivalents) for up to 33 months. Drinking PJ was associated with statistically significant increases in PSADT. After 33 months of follow-up, the median PSADT increased from 11.5 months to 28.7 months (P < .001). In addition, LNCaP cells were treated in vitro with the subjects’ serum before and after the PJ intervention. Results of the in vitro experiments showed a decrease in cell growth and an increase in apoptosis following PJ treatment.[18]

A phase II study evaluated 1-g and 3-g doses of pomegranate extract in 104 men with rising PSA values following initial therapy for localized prostate cancer.[19] The study reported that pomegranate extract was associated with an increase of at least 6 months in PSADT in both treatment arms, without adverse effects. However, a phase III placebo-controlled trial of 183 patients who were randomly assigned to the pomegranate juice, pomegranate extract, or placebo did not significantly prolong PSADT in prostate cancer patients with rising PSA after primary therapy.[20] Some data from this study suggest that a subgroup analysis should be done to further investigate a potential unique sensitivity.

Adverse Effects

In a study of prostate cancer patients reported in 2006, the PJ intervention was well tolerated and no serious adverse effects were observed.[18]

In a pilot study reported in 2007, the safety of PJ in patients with erectile dysfunction was examined. No serious adverse effects were observed during this study, and no participant dropped out due to adverse side effects. In the analysis of the results, no statistical comparisons were made of the adverse side effects observed in the intervention arm and the placebo arm.[21]

References

1. Jurenka JS: Therapeutic applications of pomegranate (Punica granatum L.): a review. Altern Med Rev 13 (2): 128-44, 2008. [PubMed: 18590349]
2. Langley P: Why a pomegranate? BMJ 321 (7269): 1153-4, 2000. [PMC free article: PMC1118911] [PubMed: 11061746]
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 April 19, 2016. [PubMed: 33467822]
4. Basu A, Penugonda K: Pomegranate juice: a heart-healthy fruit juice. Nutr Rev 67 (1): 49-56, 2009. [PubMed: 19146506]
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. [PubMed: 15158307]
6. Menezes SM, Cordeiro LN, Viana GS: Punica granatum (pomegranate) extract is active against dental plaque. J Herb Pharmacother 6 (2): 79-92, 2006. [PubMed: 17182487]
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. [PubMed: 17722872]
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. [PubMed: 15383219]
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 58 (23): 12149-56, 2010. [PubMed: 21067181]
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. [PMC free article: PMC2610864] [PubMed: 18479901]
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. [PubMed: 15528976]
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. [PMC free article: PMC2815223] [PubMed: 19853487]
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. [PMC free article: PMC1253570] [PubMed: 16192356]
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. [PubMed: 19919114]
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. [PubMed: 21594291]
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. [PubMed: 18202771]
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. [PMC free article: PMC3291862] [PubMed: 22198212]
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. [PubMed: 16818701]
19. Paller CJ, Ye X, Wozniak PJ, et al.: A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis 16 (1): 50-5, 2013. [PMC free article: PMC3549301] [PubMed: 22689129]
20. Pantuck AJ, Pettaway CA, Dreicer R, et al.: A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising PSA levels in men following primary therapy for prostate cancer. Prostate Cancer Prostatic Dis 18 (3): 242-8, 2015. [PubMed: 26169045]
21. 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. [PubMed: 17568759]

Overview

This section contains the following key information:

• Selenium is an essential trace mineral involved in a number of biological processes, including kinase regulation, gene expression, and immune function.
• Animal and epidemiological studies have suggested there may be an inverse relationship between selenium supplementation and cancer risk.
• The results of epidemiologic studies suggest some complexity in the association between blood levels of selenium and the risk of developing prostate cancer.
• The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large multicenter clinical trial, was initiated to examine the effects of selenium and/or vitamin E on the development of prostate cancer.
• Initial results of SELECT, published in 2009, showed no statistically significant difference in the rate of prostate cancer in men who were randomly assigned to receive the selenium supplements.
• In 2011, updated results from SELECT showed no significant effects of selenium supplementation on risk, but men who took vitamin E alone had a 17% increase in prostate cancer risk compared with men who took placebo.
• In 2014, an analysis of SELECT results showed that men who had high selenium status at baseline and who were randomly assigned to receive selenium supplementation had an increased risk of high-grade prostate cancer.

General Information and History

Selenium is an essential trace mineral involved in a number of biological processes, including enzyme regulation, gene expression, and immune function. Selenium was discovered in 1818 and named after the Greek goddess of the moon, Selene.[1] A number of selenoproteins have been identified in humans, including selenoprotein P (SEPP), which is the main selenium carrier in the body and is important for selenium homeostasis.

Food sources of selenium include meat, vegetables, and nuts. The selenium content of the soil where food is raised determines the amount of selenium found in plants and animals. For adults, the recommended daily allowance for selenium is 55 µg/d.[2] Most dietary selenium occurs as selenocysteine or selenomethionine.[1] Selenium accumulates in the thyroid gland, liver, pancreas, pituitary gland, and renal medulla.[3]

Selenium is a component of the enzyme glutathione peroxidase, an enzyme that functions as an antioxidant.[4] However, at high concentrations, selenium may function as a pro-oxidant.[2]

Selenium is implicated in a number of disease states. Selenium deficiency may result in Keshan disease, a form of childhood cardiomyopathy, and Kaskin-Beck disease, a bone disorder.[5] Some clinical trials have suggested that high levels of selenium may be associated with diabetes [6] and high cholesterol.[2]

Selenium may also play a role in cancer. Animal and epidemiological studies have suggested there may be an inverse relationship between selenium supplementation and cancer risk.[7] The Nutritional Prevention of Cancer Trial (NPC) was a randomized, placebo-controlled study designed to test the hypothesis that higher selenium levels were associated with lower incidence of skin cancer. The results indicated that selenium supplementation did not affect risk of skin cancer, although incidences of lung, colorectal, and prostate cancer were significantly reduced.[8]

There is evidence that selenoproteins may be associated with carcinogenesis. For example, reduced expression of glutathione peroxidase 3 and selenoprotein P have been observed in some tumors, while increased expression of glutathione peroxidase 2 occurs in colorectal and lung tumors.[7]

Preclinical/Animal Studies

Human Studies

Adverse Effects

Selenium supplementation was well tolerated in many clinical trials. In two published trials, there were no differences reported in adverse effects between placebo or treatment groups.[34,35] However, in SELECT, selenium supplementation was associated with a nonsignificant increase in incidence of diabetes mellitus (P = .08).[39]

References

1. Brown KM, Arthur JR: Selenium, selenoproteins and human health: a review. Public Health Nutr 4 (2B): 593-9, 2001. [PubMed: 11683552]
2. Tanguy S, Grauzam S, de Leiris J, et al.: Impact of dietary selenium intake on cardiac health: experimental approaches and human studies. Mol Nutr Food Res 56 (7): 1106-21, 2012. [PubMed: 22760983]
3. Mordan-McCombs S, Brown T, Zinser G, et al.: Dietary calcium does not affect prostate tumor progression in LPB-Tag transgenic mice. J Steroid Biochem Mol Biol 103 (3-5): 747-51, 2007. [PMC free article: PMC1950667] [PubMed: 17307354]
4. Bodnar M, Konieczka P, Namiesnik J: The properties, functions, and use of selenium compounds in living organisms. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 30 (3): 225-52, 2012. [PubMed: 22970720]
5. Sunde RA: Selenium. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 711-8.
6. Boosalis MG: The role of selenium in chronic disease. Nutr Clin Pract 23 (2): 152-60, 2008 Apr-May. [PubMed: 18390782]
7. Davis CD, Tsuji PA, Milner JA: Selenoproteins and cancer prevention. Annu Rev Nutr 32: 73-95, 2012. [PubMed: 22404120]
8. Clark LC, Combs GF Jr, Turnbull BW, et al.: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276 (24): 1957-63, 1996. [PubMed: 8971064]
9. Pinto JT, Sinha R, Papp K, et al.: Differential effects of naturally occurring and synthetic organoselenium compounds on biomarkers in androgen responsive and androgen independent human prostate carcinoma cells. Int J Cancer 120 (7): 1410-7, 2007. [PubMed: 17205524]
10. Lunøe K, Gabel-Jensen C, Stürup S, et al.: Investigation of the selenium metabolism in cancer cell lines. Metallomics 3 (2): 162-8, 2011. [PubMed: 21161099]
11. Kong L, Yuan Q, Zhu H, et al.: The suppression of prostate LNCaP cancer cells growth by Selenium nanoparticles through Akt/Mdm2/AR controlled apoptosis. Biomaterials 32 (27): 6515-22, 2011. [PubMed: 21640377]
12. Sarveswaran S, Liroff J, Zhou Z, et al.: Selenite triggers rapid transcriptional activation of p53, and p53-mediated apoptosis in prostate cancer cells: Implication for the treatment of early-stage prostate cancer. Int J Oncol 36 (6): 1419-28, 2010. [PubMed: 20428765]
13. Xiang N, Zhao R, Zhong W: Sodium selenite induces apoptosis by generation of superoxide via the mitochondrial-dependent pathway in human prostate cancer cells. Cancer Chemother Pharmacol 63 (2): 351-62, 2009. [PMC free article: PMC2592502] [PubMed: 18379781]
14. Kandaş NO, Randolph C, Bosland MC: Differential effects of selenium on benign and malignant prostate epithelial cells: stimulation of LNCaP cell growth by noncytotoxic, low selenite concentrations. Nutr Cancer 61 (2): 251-64, 2009. [PMC free article: PMC2821820] [PubMed: 19235042]
15. Niskar AS, Paschal DC, Kieszak SM, et al.: Serum selenium levels in the US population: Third National Health and Nutrition Examination Survey, 1988-1994. Biol Trace Elem Res 91 (1): 1-10, 2003. [PubMed: 12713024]
16. Takata Y, Morris JS, King IB, et al.: Correlation between selenium concentrations and glutathione peroxidase activity in serum and human prostate tissue. Prostate 69 (15): 1635-42, 2009. [PMC free article: PMC3166332] [PubMed: 19623542]
17. Waters DJ, Shen S, Kengeri SS, et al.: Prostatic response to supranutritional selenium supplementation: comparison of the target tissue potency of selenomethionine vs. selenium-yeast on markers of prostatic homeostasis. Nutrients 4 (11): 1650-63, 2012. [PMC free article: PMC3509511] [PubMed: 23201838]
18. Li GX, Lee HJ, Wang Z, et al.: Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite. Carcinogenesis 29 (5): 1005-12, 2008. [PMC free article: PMC3312608] [PubMed: 18310093]
19. Holmstrom A, Wu RT, Zeng H, et al.: Nutritional and supranutritional levels of selenate differentially suppress prostate tumor growth in adult but not young nude mice. J Nutr Biochem 23 (9): 1086-91, 2012. [PubMed: 22137259]
20. Wang L, Bonorden MJ, Li GX, et al.: Methyl-selenium compounds inhibit prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit. Cancer Prev Res (Phila) 2 (5): 484-95, 2009. [PMC free article: PMC2822708] [PubMed: 19401524]
21. Zhang J, Wang L, Anderson LB, et al.: Proteomic profiling of potential molecular targets of methyl-selenium compounds in the transgenic adenocarcinoma of mouse prostate model. Cancer Prev Res (Phila) 3 (8): 994-1006, 2010. [PubMed: 20647336]
22. Gundimeda U, Schiffman JE, Chhabra D, et al.: Locally generated methylseleninic acid induces specific inactivation of protein kinase C isoenzymes: relevance to selenium-induced apoptosis in prostate cancer cells. J Biol Chem 283 (50): 34519-31, 2008. [PMC free article: PMC3259896] [PubMed: 18922790]
23. Steinbrecher A, Méplan C, Hesketh J, et al.: Effects of selenium status and polymorphisms in selenoprotein genes on prostate cancer risk in a prospective study of European men. Cancer Epidemiol Biomarkers Prev 19 (11): 2958-68, 2010. [PubMed: 20852007]
24. Muecke R, Klotz T, Giedl J, et al.: Whole blood selenium levels (WBSL) in patients with prostate cancer (PC), benign prostatic hyperplasia (BPH) and healthy male inhabitants (HMI) and prostatic tissue selenium levels (PTSL) in patients with PC and BPH. Acta Oncol 48 (3): 452-6, 2009. [PubMed: 18855158]
25. Chan JM, Oh WK, Xie W, et al.: Plasma selenium, manganese superoxide dismutase, and intermediate- or high-risk prostate cancer. J Clin Oncol 27 (22): 3577-83, 2009. [PMC free article: PMC2720077] [PubMed: 19528373]
26. Méplan C, Rohrmann S, Steinbrecher A, et al.: Polymorphisms in thioredoxin reductase and selenoprotein K genes and selenium status modulate risk of prostate cancer. PLoS One 7 (11): e48709, 2012. [PMC free article: PMC3486803] [PubMed: 23133653]
27. Geybels MS, Hutter CM, Kwon EM, et al.: Variation in selenoenzyme genes and prostate cancer risk and survival. Prostate 73 (7): 734-42, 2013. [PMC free article: PMC3859305] [PubMed: 23143801]
28. Meyer HA, Hollenbach B, Stephan C, et al.: Reduced serum selenoprotein P concentrations in German prostate cancer patients. Cancer Epidemiol Biomarkers Prev 18 (9): 2386-90, 2009. [PubMed: 19690186]
29. Penney KL, Li H, Mucci LA, et al.: Selenoprotein P genetic variants and mrna expression, circulating selenium, and prostate cancer risk and survival. Prostate 73 (7): 700-5, 2013. [PMC free article: PMC3640488] [PubMed: 23129481]
30. Kenfield SA, Van Blarigan EL, DuPre N, et al.: Selenium supplementation and prostate cancer mortality. J Natl Cancer Inst 107 (1): 360, 2015. [PMC free article: PMC4296194] [PubMed: 25505227]
31. Zhang W, Joseph E, Hitchcock C, et al.: Selenium glycinate supplementation increases blood glutathione peroxidase activities and decreases prostate-specific antigen readings in middle-aged US men. Nutr Res 31 (2): 165-8, 2011. [PubMed: 21419321]
32. Hurst R, Hooper L, Norat T, et al.: Selenium and prostate cancer: systematic review and meta-analysis. Am J Clin Nutr 96 (1): 111-22, 2012. [PubMed: 22648711]
33. Vidlar A, Vostalova J, Ulrichova J, et al.: The safety and efficacy of a silymarin and selenium combination in men after radical prostatectomy - a six month placebo-controlled double-blind clinical trial. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 154 (3): 239-44, 2010. [PubMed: 21048810]
34. Stratton MS, Algotar AM, Ranger-Moore J, et al.: Oral selenium supplementation has no effect on prostate-specific antigen velocity in men undergoing active surveillance for localized prostate cancer. Cancer Prev Res (Phila) 3 (8): 1035-43, 2010. [PMC free article: PMC4533875] [PubMed: 20647337]
35. Algotar AM, Stratton MS, Ahmann FR, et al.: Phase 3 clinical trial investigating the effect of selenium supplementation in men at high-risk for prostate cancer. Prostate 73 (3): 328-35, 2013. [PMC free article: PMC4086804] [PubMed: 22887343]
36. Marshall JR, Tangen CM, Sakr WA, et al.: Phase III trial of selenium to prevent prostate cancer in men with high-grade prostatic intraepithelial neoplasia: SWOG S9917. Cancer Prev Res (Phila) 4 (11): 1761-9, 2011. [PMC free article: PMC3208719] [PubMed: 21896650]
37. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [PubMed: 8127329]
38. Klein EA: Selenium and vitamin E cancer prevention trial. Ann N Y Acad Sci 1031: 234-41, 2004. [PubMed: 15753149]
39. Lippman SM, Klein EA, Goodman PJ, et al.: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301 (1): 39-51, 2009. [PMC free article: PMC3682779] [PubMed: 19066370]
40. Klein EA, Thompson IM Jr, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011. [PMC free article: PMC4169010] [PubMed: 21990298]
41. Lippman SM, Goodman PJ, Klein EA, et al.: Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). J Natl Cancer Inst 97 (2): 94-102, 2005. [PubMed: 15657339]
42. Ledesma MC, Jung-Hynes B, Schmit TL, et al.: Selenium and vitamin E for prostate cancer: post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) status. Mol Med 17 (1-2): 134-43, 2011 Jan-Feb. [PMC free article: PMC3022975] [PubMed: 20882260]
43. Hatfield DL, Gladyshev VN: The Outcome of Selenium and Vitamin E Cancer Prevention Trial (SELECT) reveals the need for better understanding of selenium biology. Mol Interv 9 (1): 18-21, 2009. [PMC free article: PMC2718722] [PubMed: 19299660]
44. Ohta Y, Kobayashi Y, Konishi S, et al.: Speciation analysis of selenium metabolites in urine and breath by HPLC- and GC-inductively coupled plasma-MS after administration of selenomethionine and methylselenocysteine to rats. Chem Res Toxicol 22 (11): 1795-801, 2009. [PubMed: 19715347]
45. Kristal AR, Darke AK, Morris JS, et al.: Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J Natl Cancer Inst 106 (3): djt456, 2014. [PMC free article: PMC3975165] [PubMed: 24563519]

Overview

This section contains the following key information:

• Soy foods (e.g., soy milk, miso, tofu, and soy flour) contain phytochemicals that may have health benefits and, among these, soy isoflavones have been the focus of most of the research.
• Soy isoflavones are phytoestrogens. The major isoflavones in soybeans are genistein (the most abundant), daidzein, and glycitein.
• Genistein affects components of multiple growth and proliferation-related pathways in prostate cancer cells, including the COX-2/prostaglandin, epidermal growth factor (EGF), and insulin-like growth factor (IGF) pathways.
• Some preclinical studies have indicated that the combined effect of multiple isoflavones may be greater than that of a single isoflavone.
• Some animal studies have demonstrated prostate cancer prevention effects with soy and genistein; however, other animal studies have yielded conflicting results regarding beneficial effects of genistein on prostate cancer metastasis.
• Epidemiologic studies have generally found high consumption of nonfermented soy foods to be associated with a decreased risk of prostate cancer.
• Limited human prevention studies have been conducted, and, so far, they have not yielded consistent or definitive findings.
• Treatment trials of various doses and preparations of soy isoflavones in men with prostate cancer have yielded varying results but have generally failed to demonstrate significant effects on prostate-specific antigen (PSA) levels.
• A few clinical trials of soy protein or whole soy products have provided preliminary evidence of the ability of these products to lower PSA levels in men with prostate cancer.
• Soy products are generally well tolerated in patients with prostate cancer. In clinical trials, the most commonly reported side effects were mild gastrointestinal symptoms.

General Information & History

Although records of soy use in China date back to the eleventh century BC, it was not until the 18th century that the plant reached Europe and the United States. The soybean is an incredibly versatile plant: it can be processed into a variety of products including soy milk, miso, tofu, soy flour, and soy oil.[1]

Soy foods contain a number of phytochemicals that may have health benefits but isoflavones have garnered the most attention. Among the isoflavones found in soybeans, genistein is the most abundant and may have the most biological activity.[2] Other isoflavones found in soy include daidzein and glycitein.[3] Isoflavones help soybeans survive in times of stress and have antioxidant, antimicrobial, and antifungal properties.[4]

Isoflavones are quickly taken up by the gut and can be detected in plasma as soon as 30 minutes after the consumption of soy products. Studies suggest that maximum levels of isoflavone plasma concentration may be achieved by 6 hours following soy product consumption.[5] Isoflavones are phytoestrogens (they bind to estrogen receptors) with a greater binding affinity for estrogen receptor beta than for estrogen receptor alpha.[6]

Some studies suggest that soy may have health benefits, including decreasing risk of cardiovascular disease and cancer. A link between isoflavones and cancer was discovered in 1987 when it was shown that genistein inhibited a protein tyrosine kinase that is often overexpressed in cancer cells.[7] Subsequently, genistein was found to inhibit multiple protein tyrosine kinases relevant to cancer cell proliferation.[8] In addition, numerous studies have shown that prostate cancer incidence is very low in Asian countries, where diets tend to be high in soy.[9]

Preclinical/Animal Studies

Human Studies

Numerous clinical studies have been conducted examining the impact of soy use on indicators of the effectiveness of prostate cancer prevention or treatment approaches. These studies have included a wide range of participants (from healthy control subjects to prostate cancer patients at various stages of the disease) and have used a number of different interventions such as soy supplements, beverages, and breads.

Adverse Effects

Overall, soy was well tolerated in clinical studies of prostate cancer patients.[24,27,29,31,38,41] The most commonly reported side effects were gastrointestinal symptoms.[28,30,31] In addition, one study reported that a participant withdrew due to insomnia.[28]

References

1. Barnes S: The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products. Lymphat Res Biol 8 (1): 89-98, 2010. [PMC free article: PMC2883528] [PubMed: 20235891]
2. Omoni AO, Aluko RE: Soybean foods and their benefits: potential mechanisms of action. Nutr Rev 63 (8): 272-83, 2005. [PubMed: 16190314]
3. Jian L: Soy, isoflavones, and prostate cancer. Mol Nutr Food Res 53 (2): 217-26, 2009. [PubMed: 18985655]
4. Messina M: A brief historical overview of the past two decades of soy and isoflavone research. J Nutr 140 (7): 1350S-4S, 2010. [PubMed: 20484551]
5. Andres S, Abraham K, Appel KE, et al.: Risks and benefits of dietary isoflavones for cancer. Crit Rev Toxicol 41 (6): 463-506, 2011. [PubMed: 21438720]
6. Messina M: Isoflavones. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 439-49.
7. Messina M: Insights gained from 20 years of soy research. J Nutr 140 (12): 2289S-2295S, 2010. [PubMed: 20980639]
8. Bektic J, Guggenberger R, Eder IE, et al.: Molecular effects of the isoflavonoid genistein in prostate cancer. Clin Prostate Cancer 4 (2): 124-9, 2005. [PubMed: 16197614]
9. Perabo FG, Von Löw EC, Ellinger J, et al.: Soy isoflavone genistein in prevention and treatment of prostate cancer. Prostate Cancer Prostatic Dis 11 (1): 6-12, 2008. [PubMed: 17923857]
10. Swami S, Krishnan AV, Moreno J, et al.: Inhibition of prostaglandin synthesis and actions by genistein in human prostate cancer cells and by soy isoflavones in prostate cancer patients. Int J Cancer 124 (9): 2050-9, 2009. [PMC free article: PMC4777303] [PubMed: 19127598]
11. Rabiau N, Kossaï M, Braud M, et al.: Genistein and daidzein act on a panel of genes implicated in cell cycle and angiogenesis by polymerase chain reaction arrays in human prostate cancer cell lines. Cancer Epidemiol 34 (2): 200-6, 2010. [PubMed: 20097631]
12. Ajdžanović V, Mojić M, Maksimović-Ivanić D, et al.: Membrane fluidity, invasiveness and dynamic phenotype of metastatic prostate cancer cells after treatment with soy isoflavones. J Membr Biol 246 (4): 307-14, 2013. [PubMed: 23417033]
13. Hsu A, Bray TM, Helferich WG, et al.: Differential effects of whole soy extract and soy isoflavones on apoptosis in prostate cancer cells. Exp Biol Med (Maywood) 235 (1): 90-7, 2010. [PMC free article: PMC4125131] [PubMed: 20404023]
14. Kumar R, Verma V, Jain A, et al.: Synergistic chemoprotective mechanisms of dietary phytoestrogens in a select combination against prostate cancer. J Nutr Biochem 22 (8): 723-31, 2011. [PubMed: 21062672]
15. Ide H, Tokiwa S, Sakamaki K, et al.: Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate 70 (10): 1127-33, 2010. [PubMed: 20503397]
16. Wang J, Eltoum IE, Lamartiniere CA: Genistein alters growth factor signaling in transgenic prostate model (TRAMP). Mol Cell Endocrinol 219 (1-2): 171-80, 2004. [PubMed: 15149738]
17. El Touny LH, Banerjee PP: Identification of a biphasic role for genistein in the regulation of prostate cancer growth and metastasis. Cancer Res 69 (8): 3695-703, 2009. [PMC free article: PMC2669842] [PubMed: 19351854]
18. Lakshman M, Xu L, Ananthanarayanan V, et al.: Dietary genistein inhibits metastasis of human prostate cancer in mice. Cancer Res 68 (6): 2024-32, 2008. [PubMed: 18339885]
19. Nakamura H, Wang Y, Kurita T, et al.: Genistein increases epidermal growth factor receptor signaling and promotes tumor progression in advanced human prostate cancer. PLoS One 6 (5): e20034, 2011. [PMC free article: PMC3095647] [PubMed: 21603581]
20. Raffoul JJ, Banerjee S, Che M, et al.: Soy isoflavones enhance radiotherapy in a metastatic prostate cancer model. Int J Cancer 120 (11): 2491-8, 2007. [PubMed: 17304503]
21. Hwang YW, Kim SY, Jee SH, et al.: Soy food consumption and risk of prostate cancer: a meta-analysis of observational studies. Nutr Cancer 61 (5): 598-606, 2009. [PubMed: 19838933]
22. van Die MD, Bone KM, Williams SG, et al.: Soy and soy isoflavones in prostate cancer: a systematic review and meta-analysis of randomized controlled trials. BJU Int 113 (5b): E119-30, 2014. [PubMed: 24053483]
23. Jackson MD, McFarlane-Anderson ND, Simon GA, et al.: Urinary phytoestrogens and risk of prostate cancer in Jamaican men. Cancer Causes Control 21 (12): 2249-57, 2010. [PubMed: 20924663]
24. Maskarinec G, Morimoto Y, Hebshi S, et al.: Serum prostate-specific antigen but not testosterone levels decrease in a randomized soy intervention among men. Eur J Clin Nutr 60 (12): 1423-9, 2006. [PubMed: 16775579]
25. Hamilton-Reeves JM, Rebello SA, Thomas W, et al.: Effects of soy protein isolate consumption on prostate cancer biomarkers in men with HGPIN, ASAP, and low-grade prostate cancer. Nutr Cancer 60 (1): 7-13, 2008. [PubMed: 18444130]
26. Miyanaga N, Akaza H, Hinotsu S, et al.: Prostate cancer chemoprevention study: an investigative randomized control study using purified isoflavones in men with rising prostate-specific antigen. Cancer Sci 103 (1): 125-30, 2012. [PubMed: 21988617]
27. Engelhardt PF, Riedl CR: Effects of one-year treatment with isoflavone extract from red clover on prostate, liver function, sexual function, and quality of life in men with elevated PSA levels and negative prostate biopsy findings. Urology 71 (2): 185-90; discussion 190, 2008. [PubMed: 18308079]
28. Kwan W, Duncan G, Van Patten C, et al.: A phase II trial of a soy beverage for subjects without clinical disease with rising prostate-specific antigen after radical radiation for prostate cancer. Nutr Cancer 62 (2): 198-207, 2010. [PubMed: 20099194]
29. Pendleton JM, Tan WW, Anai S, et al.: Phase II trial of isoflavone in prostate-specific antigen recurrent prostate cancer after previous local therapy. BMC Cancer 8: 132, 2008. [PMC free article: PMC2394534] [PubMed: 18471323]
30. deVere White RW, Hackman RM, Soares SE, et al.: Effects of a genistein-rich extract on PSA levels in men with a history of prostate cancer. Urology 63 (2): 259-63, 2004. [PubMed: 14972467]
31. deVere White RW, Tsodikov A, Stapp EC, et al.: Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone concentrations in men with localized prostate cancer. Nutr Cancer 62 (8): 1036-43, 2010. [PMC free article: PMC2993162] [PubMed: 21058191]
32. Lazarevic B, Boezelijn G, Diep LM, et al.: Efficacy and safety of short-term genistein intervention in patients with localized prostate cancer prior to radical prostatectomy: a randomized, placebo-controlled, double-blind Phase 2 clinical trial. Nutr Cancer 63 (6): 889-98, 2011. [PubMed: 21714686]
33. Hamilton-Reeves JM, Banerjee S, Banerjee SK, et al.: Short-term soy isoflavone intervention in patients with localized prostate cancer: a randomized, double-blind, placebo-controlled trial. PLoS One 8 (7): e68331, 2013. [PMC free article: PMC3710024] [PubMed: 23874588]
34. Kumar NB, Krischer JP, Allen K, et al.: A Phase II randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer. Nutr Cancer 59 (2): 163-8, 2007. [PMC free article: PMC2435485] [PubMed: 18001210]
35. Kumar NB, Krischer JP, Allen K, et al.: Safety of purified isoflavones in men with clinically localized prostate cancer. Nutr Cancer 59 (2): 169-75, 2007. [PMC free article: PMC2442460] [PubMed: 18001211]
36. Kumar NB, Kang L, Pow-Sang J, et al.: Results of a randomized phase I dose-finding trial of several doses of isoflavones in men with localized prostate cancer: administration prior to radical prostatectomy. J Soc Integr Oncol 8 (1): 3-13, 2010. [PMC free article: PMC3277948] [PubMed: 20205984]
37. Kumar NB, Cantor A, Allen K, et al.: The specific role of isoflavones in reducing prostate cancer risk. Prostate 59 (2): 141-7, 2004. [PubMed: 15042614]
38. Gardner CD, Oelrich B, Liu JP, et al.: Prostatic soy isoflavone concentrations exceed serum levels after dietary supplementation. Prostate 69 (7): 719-26, 2009. [PMC free article: PMC2734961] [PubMed: 19180569]
39. Dalais FS, Meliala A, Wattanapenpaiboon N, et al.: Effects of a diet rich in phytoestrogens on prostate-specific antigen and sex hormones in men diagnosed with prostate cancer. Urology 64 (3): 510-5, 2004. [PubMed: 15351581]
40. Joshi M, Agostino NM, Gingrich R, et al.: Effects of commercially available soy products on PSA in androgen-deprivation-naïve and castration-resistant prostate cancer. South Med J 104 (11): 736-40, 2011. [PubMed: 22024780]
41. Sharma P, Wisniewski A, Braga-Basaria M, et al.: Lack of an effect of high dose isoflavones in men with prostate cancer undergoing androgen deprivation therapy. J Urol 182 (5): 2265-72, 2009. [PMC free article: PMC3089061] [PubMed: 19758646]
42. Vitolins MZ, Griffin L, Tomlinson WV, et al.: Randomized trial to assess the impact of venlafaxine and soy protein on hot flashes and quality of life in men with prostate cancer. J Clin Oncol 31 (32): 4092-8, 2013. [PMC free article: PMC3816959] [PubMed: 24081940]
43. Napora JK, Short RG, Muller DC, et al.: High-dose isoflavones do not improve metabolic and inflammatory parameters in androgen-deprived men with prostate cancer. J Androl 32 (1): 40-8, 2011 Jan-Feb. [PMC free article: PMC3005077] [PubMed: 20798386]

Overview

• Vitamin D is made naturally by the body when exposed to sunlight.
• Preclinical studies suggest that vitamin D may have effects on prostate cancer cells through various pathways.
• Numerous epidemiological studies have researched the relationship between vitamin D and prostate cancer.
• Some intervention studies have focused on calcitriol, the hormonally active form of vitamin D, in prostate cancer patients.

General Information and History

Vitamin D, also called calciferol, cholecalciferol (D3), or ergocalciferol (D2), is a fat-soluble vitamin found in fortified dairy products, fatty fish, fish liver oil, and eggs. Vitamin D is made naturally by the body when exposed to sunlight.

In 1922, researchers discovered that heated, oxidized cod-liver oil, called "fat-soluble factor A" and later known as vitamin D, played an important role in curing rickets in rats.[1]

Vitamin D performs many roles in the body, including the following:

• Promoting absorption of calcium in the small intestine.
• Improving muscle strength and immune function.
• Helping to reduce inflammation.
• Helping to maintain adequate blood levels of calcium and phosphate.

Vitamin D is needed for bone growth and protects against osteoporosis in adults.[2] Vitamin D status is usually checked by measuring the level of 25-hydroxyvitamin D in the blood.

Preclinical/Animal Studies

Human Studies

Adverse Effects

References

1. Wolf G: The discovery of vitamin D: the contribution of Adolf Windaus. J Nutr 134 (6): 1299-302, 2004. [PubMed: 15173387]
2. National Institutes of Health. Office of Dietary Supplements: Dietary Supplement Fact Sheet: Vitamin D. Bethesda, MD: National Institutes of Health, 2011. Available online. Last accessed April 19, 2016.
3. Hsu JW, Yasmin-Karim S, King MR, et al.: Suppression of prostate cancer cell rolling and adhesion to endothelium by 1α,25-dihydroxyvitamin D3. Am J Pathol 178 (2): 872-80, 2011. [PMC free article: PMC3069912] [PubMed: 21281819]
4. Gregory KJ, Zhao B, Bielenberg DR, et al.: Vitamin D binding protein-macrophage activating factor directly inhibits proliferation, migration, and uPAR expression of prostate cancer cells. PLoS One 5 (10): e13428, 2010. [PMC free article: PMC2956649] [PubMed: 20976141]
5. Karlsson S, Olausson J, Lundh D, et al.: Vitamin D and prostate cancer: the role of membrane initiated signaling pathways in prostate cancer progression. J Steroid Biochem Mol Biol 121 (1-2): 413-6, 2010. [PubMed: 20398754]
6. Mordan-McCombs S, Brown T, Wang WL, et al.: Tumor progression in the LPB-Tag transgenic model of prostate cancer is altered by vitamin D receptor and serum testosterone status. J Steroid Biochem Mol Biol 121 (1-2): 368-71, 2010. [PMC free article: PMC4211603] [PubMed: 20347977]
7. Zheng Y, Zhou H, Ooi LL, et al.: Vitamin D deficiency promotes prostate cancer growth in bone. Prostate 71 (9): 1012-21, 2011. [PubMed: 21541977]
8. Ajibade AA, Kirk JS, Karasik E, et al.: Early growth inhibition is followed by increased metastatic disease with vitamin D (calcitriol) treatment in the TRAMP model of prostate cancer. PLoS One 9 (2): e89555, 2014. [PMC free article: PMC3935875] [PubMed: 24586868]
9. Ahn J, Peters U, Albanes D, et al.: Serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst 100 (11): 796-804, 2008. [PMC free article: PMC3703748] [PubMed: 18505967]
10. Kimura M, Rabbani Z, Mouraviev V, et al.: Role of vitamin D(3) as a sensitizer to cryoablation in a murine prostate cancer model: preliminary in vivo study. Urology 76 (3): 764.e14-20, 2010. [PubMed: 20599255]
11. Santucci KL, Snyder KK, Baust JM, et al.: Use of 1,25α dihydroxyvitamin D3 as a cryosensitizing agent in a murine prostate cancer model. Prostate Cancer Prostatic Dis 14 (2): 97-104, 2011. [PMC free article: PMC3094482] [PubMed: 21221127]
12. Gavrilov V, Leibovich Y, Ariad S, et al.: A combined pretreatment of 1,25-dihydroxyvitamin D3 and sodium valproate enhances the damaging effect of ionizing radiation on prostate cancer cells. J Steroid Biochem Mol Biol 121 (1-2): 391-4, 2010. [PubMed: 20214985]
13. Choo CS, Mamedov A, Chung M, et al.: Vitamin D insufficiency is common in patients with nonmetastatic prostate cancer. Nutr Res 31 (1): 21-6, 2011. [PubMed: 21310302]
14. Fang F, Kasperzyk JL, Shui I, et al.: Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer. PLoS One 6 (4): e18625, 2011. [PMC free article: PMC3071841] [PubMed: 21494639]
15. Tretli S, Hernes E, Berg JP, et al.: Association between serum 25(OH)D and death from prostate cancer. Br J Cancer 100 (3): 450-4, 2009. [PMC free article: PMC2658536] [PubMed: 19156140]
16. Albanes D, Mondul AM, Yu K, et al.: Serum 25-hydroxy vitamin D and prostate cancer risk in a large nested case-control study. Cancer Epidemiol Biomarkers Prev 20 (9): 1850-60, 2011. [PMC free article: PMC3188814] [PubMed: 21784952]
17. Xu Y, Shao X, Yao Y, et al.: Positive association between circulating 25-hydroxyvitamin D levels and prostate cancer risk: new findings from an updated meta-analysis. J Cancer Res Clin Oncol 140 (9): 1465-77, 2014. [PubMed: 24838848]
18. Murphy AB, Nyame Y, Martin IK, et al.: Vitamin D deficiency predicts prostate biopsy outcomes. Clin Cancer Res 20 (9): 2289-99, 2014. [PMC free article: PMC4104275] [PubMed: 24789033]
19. Kristal AR, Till C, Song X, et al.: Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 23 (8): 1494-504, 2014. [PMC free article: PMC4119495] [PubMed: 24732629]
20. Vieth R, Choo R, Deboer L, et al.: Rise in prostate-specific antigen in men with untreated low-grade prostate cancer is slower during spring-summer. Am J Ther 13 (5): 394-9, 2006 Sep-Oct. [PubMed: 16988533]
21. Gilbert R, Metcalfe C, Oliver SE, et al.: Life course sun exposure and risk of prostate cancer: population-based nested case-control study and meta-analysis. Int J Cancer 125 (6): 1414-23, 2009. [PMC free article: PMC2873563] [PubMed: 19444909]
22. Schwartz GG, Hanchette CL: UV, latitude, and spatial trends in prostate cancer mortality: all sunlight is not the same (United States). Cancer Causes Control 17 (8): 1091-101, 2006. [PubMed: 16933060]
23. Grant WB: An ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. Dermatoendocrinol 2 (2): 62-7, 2010. [PMC free article: PMC3081677] [PubMed: 21547101]
24. Hendrickson WK, Flavin R, Kasperzyk JL, et al.: Vitamin D receptor protein expression in tumor tissue and prostate cancer progression. J Clin Oncol 29 (17): 2378-85, 2011. [PMC free article: PMC3107752] [PubMed: 21537045]
25. Chen L, Davey Smith G, Evans DM, et al.: Genetic variants in the vitamin d receptor are associated with advanced prostate cancer at diagnosis: findings from the prostate testing for cancer and treatment study and a systematic review. Cancer Epidemiol Biomarkers Prev 18 (11): 2874-81, 2009. [PubMed: 19861519]
26. Holt SK, Kwon EM, Koopmeiners JS, et al.: Vitamin D pathway gene variants and prostate cancer prognosis. Prostate 70 (13): 1448-60, 2010. [PMC free article: PMC2927712] [PubMed: 20687218]
27. Gilbert R, Bonilla C, Metcalfe C, et al.: Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer: a nested case-control study. Cancer Causes Control 26 (2): 205-18, 2015. [PMC free article: PMC4298668] [PubMed: 25488826]
28. Shui IM, Mondul AM, Lindström S, et al.: Circulating vitamin D, vitamin D-related genetic variation, and risk of fatal prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. Cancer 121 (12): 1949-56, 2015. [PMC free article: PMC4457645] [PubMed: 25731953]
29. Huncharek M, Muscat J, Kupelnick B: Dairy products, dietary calcium and vitamin D intake as risk factors for prostate cancer: a meta-analysis of 26,769 cases from 45 observational studies. Nutr Cancer 60 (4): 421-41, 2008. [PubMed: 18584476]
30. Gilbert R, Martin RM, Beynon R, et al.: Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose-response meta-analysis. Cancer Causes Control 22 (3): 319-40, 2011. [PubMed: 21203822]
31. Srinivas S, Feldman D: A phase II trial of calcitriol and naproxen in recurrent prostate cancer. Anticancer Res 29 (9): 3605-10, 2009. [PubMed: 19667155]
32. Chadha MK, Tian L, Mashtare T, et al.: Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (calcitriol) in combination with dexamethasone for castration-resistant prostate cancer. Cancer 116 (9): 2132-9, 2010. [PubMed: 20166215]
33. Newsom-Davis TE, Kenny LM, Ngan S, et al.: The promiscuous receptor. BJU Int 104 (9): 1204-7, 2009. [PubMed: 19426197]
34. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press, 1997. Also available online. Last accessed April 19, 2016. [PubMed: 23115811]
35. Kennedy DA, Cooley K, Skidmore B, et al.: Vitamin d: pharmacokinetics and safety when used in conjunction with the pharmaceutical drugs used in cancer patients: a systematic review. Cancers (Basel) 5 (1): 255-80, 2013. [PMC free article: PMC3730309] [PubMed: 24216707]
36. Petrioli R, Pascucci A, Francini E, et al.: Weekly high-dose calcitriol and docetaxel in patients with metastatic hormone-refractory prostate cancer previously exposed to docetaxel. BJU Int 100 (4): 775-9, 2007. [PubMed: 17535276]
37. Tiffany NM, Ryan CW, Garzotto M, et al.: High dose pulse calcitriol, docetaxel and estramustine for androgen independent prostate cancer: a phase I/II study. J Urol 174 (3): 888-92, 2005. [PubMed: 16093981]
38. Beer TM, Eilers KM, Garzotto M, et al.: Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol 21 (1): 123-8, 2003. [PubMed: 12506180]
39. Beer TM, Ryan CW, Venner PM, et al.: Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol 25 (6): 669-74, 2007. [PubMed: 17308271]
40. Fakih MG, Trump DL, Muindi JR, et al.: A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors. Clin Cancer Res 13 (4): 1216-23, 2007. [PubMed: 17317832]
41. Muindi JR, Peng Y, Potter DM, et al.: Pharmacokinetics of high-dose oral calcitriol: results from a phase 1 trial of calcitriol and paclitaxel. Clin Pharmacol Ther 72 (6): 648-59, 2002. [PubMed: 12496746]

Overview

• Most dietary vitamin E comes from gamma-tocopherol. Food sources of vitamin E include vegetable oil, nuts, and egg yolks.
• Research suggests that vitamin E may protect against a number of chronic diseases, such as cardiovascular disease.
• Studies suggest that alpha-tocopherol–associated protein (TAP) may have capabilities as a tumor suppressor in prostate cancer.
• The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large multicenter clinical trial, was initiated by the National Institutes of Health (NIH) in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer.
• In 2011, updated results from SELECT showed that men who took vitamin E alone had a 17% increase in prostate cancer risk compared with men who took placebo.
• In 2014, an analysis of SELECT results showed that men who had high selenium status at baseline and who were randomly assigned to receive selenium supplementation had an increased risk of high-grade prostate cancer, but vitamin E supplementation had no effect among men with high selenium status.

General Information and History

Vitamin E was discovered in 1922 as a factor essential for reproduction.[1]

Vitamin E occurs in eight different forms: four tocopherols (alpha-, beta-, gamma-, and sigma-) and four tocotrienols (alpha-, beta-, gamma-, and sigma-).[2] Compared with other tocopherols, alpha-tocopherol (the form of vitamin E commonly found in dietary supplements) is the most abundant in the body and the most biologically active. Most dietary vitamin E comes from gamma-tocopherol. Food sources of vitamin E include vegetable oil, nuts, and egg yolks.[3].

The bioavailability of vitamin E depends on a number of factors, such as the food matrix containing vitamin E (e.g., low- or high-fat food).[4] Vitamin E is delivered to tissues by high- and low-density lipoproteins (HDL and LDL, respectively). Delivery by LDL occurs via an endocytic pathway, while the protein’s ATP-binding cassette, subfamily 1 (ABCA1) and scavenger receptor class B type 1 (SR-BI) are involved in HDL vitamin E transport.[5]

Research suggests that vitamin E may protect against a number of chronic diseases, such as cardiovascular disease.[1] Many of vitamin E’s health benefits have been ascribed to its actions as a powerful antioxidant; as with other antioxidants, vitamin E protects cell membranes by interfering with reactions that would form lipid hydroperoxide products.[5] Vitamin E also has nonantioxidant functions: it has been shown to modulate signaling pathways and gene expression.[3]

Human Studies

Adverse Effects

Alpha-tocopherols have been deemed Generally Recognized as Safe by the U.S. Food and Drug Administration.[26]

In the Physicians’ Health Study II, there were no significant effects reported for gastrointestinal tract symptoms, fatigue, drowsiness, skin discoloration or rashes, or migraine. However, participants who took vitamin E (400 IU of alpha-tocopherol every other day) experienced a greater number of hemorrhagic strokes than did participants who took placebo.[12] An increase in hemorrhagic strokes among participants in the vitamin E group (50 mg of alpha-tocopherol daily) also was noted in the ATBC Study.[13]

In the initial report of results from SELECT, there were no significant differences between incidences of less severe adverse effects (e.g., alopecia, dermatitis, and nausea) experienced by the groups that received vitamin E (400 IU of all rac-alpha-tocopheryl acetate per day) and those experienced by the other treatment groups.[20] Follow-up analysis of SELECT participants revealed an increased risk of prostate cancer among men in the vitamin E–alone group.[21]

References

1. Pekmezci D: Vitamin E and immunity. Vitam Horm 86: 179-215, 2011. [PubMed: 21419272]
2. Crispen PL, Uzzo RG, Golovine K, et al.: Vitamin E succinate inhibits NF-kappaB and prevents the development of a metastatic phenotype in prostate cancer cells: implications for chemoprevention. Prostate 67 (6): 582-90, 2007. [PubMed: 17262802]
3. Ni J, Yeh S: The roles of alpha-vitamin E and its analogues in prostate cancer. Vitam Horm 76: 493-518, 2007. [PubMed: 17628187]
4. Mustacich DJ, Bruno RS, Traber MG: Vitamin E. Vitam Horm 76: 1-21, 2007. [PubMed: 17628169]
5. Traber MG: Vitamin E. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 841-50.
6. Wright ME, Weinstein SJ, Lawson KA, et al.: Supplemental and dietary vitamin E intakes and risk of prostate cancer in a large prospective study. Cancer Epidemiol Biomarkers Prev 16 (6): 1128-35, 2007. [PubMed: 17548674]
7. Adaramoye OA, Akinloye O, Olatunji IK: Trace elements and vitamin E status in Nigerian patients with prostate cancer. Afr Health Sci 10 (1): 2-8, 2010. [PMC free article: PMC2895796] [PubMed: 20811517]
8. Wen XQ, Li XJ, Su ZL, et al.: Reduced expression of alpha-tocopherol-associated protein is associated with tumor cell proliferation and the increased risk of prostate cancer recurrence. Asian J Androl 9 (2): 206-12, 2007. [PubMed: 17334589]
9. Mondul AM, Rohrmann S, Menke A, et al.: Association of serum α-tocopherol with sex steroid hormones and interactions with smoking: implications for prostate cancer risk. Cancer Causes Control 22 (6): 827-36, 2011. [PMC free article: PMC3499970] [PubMed: 21424597]
10. Weinstein SJ, Peters U, Ahn J, et al.: Serum α-tocopherol and γ-tocopherol concentrations and prostate cancer risk in the PLCO Screening Trial: a nested case-control study. PLoS One 7 (7): e40204, 2012. [PMC free article: PMC3390343] [PubMed: 22792240]
11. Cui R, Liu ZQ, Xu Q: Blood α-tocopherol, γ-tocopherol levels and risk of prostate cancer: a meta-analysis of prospective studies. PLoS One 9 (3): e93044, 2014. [PMC free article: PMC3965522] [PubMed: 24667740]
12. Gaziano JM, Glynn RJ, Christen WG, et al.: Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. JAMA 301 (1): 52-62, 2009. [PMC free article: PMC2774210] [PubMed: 19066368]
13. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [PubMed: 8127329]
14. Weinstein SJ, Wright ME, Lawson KA, et al.: Serum and dietary vitamin E in relation to prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16 (6): 1253-9, 2007. [PubMed: 17548693]
15. Wright ME, Peters U, Gunter MJ, et al.: Association of variants in two vitamin e transport genes with circulating vitamin e concentrations and prostate cancer risk. Cancer Res 69 (4): 1429-38, 2009. [PMC free article: PMC2644342] [PubMed: 19190344]
16. Watters JL, Gail MH, Weinstein SJ, et al.: Associations between alpha-tocopherol, beta-carotene, and retinol and prostate cancer survival. Cancer Res 69 (9): 3833-41, 2009. [PMC free article: PMC2787239] [PubMed: 19383902]
17. Cheng TY, Barnett MJ, Kristal AR, et al.: Genetic variation in myeloperoxidase modifies the association of serum α-tocopherol with aggressive prostate cancer among current smokers. J Nutr 141 (9): 1731-7, 2011. [PMC free article: PMC3735918] [PubMed: 21795425]
18. Clark LC, Combs GF Jr, Turnbull BW, et al.: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276 (24): 1957-63, 1996. [PubMed: 8971064]
19. Klein EA: Selenium and vitamin E cancer prevention trial. Ann N Y Acad Sci 1031: 234-41, 2004. [PubMed: 15753149]
20. Lippman SM, Klein EA, Goodman PJ, et al.: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301 (1): 39-51, 2009. [PMC free article: PMC3682779] [PubMed: 19066370]
21. Klein EA, Thompson IM Jr, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011. [PMC free article: PMC4169010] [PubMed: 21990298]
22. Kristal AR, Darke AK, Morris JS, et al.: Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J Natl Cancer Inst 106 (3): djt456, 2014. [PMC free article: PMC3975165] [PubMed: 24563519]
23. Lippman SM, Goodman PJ, Klein EA, et al.: Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). J Natl Cancer Inst 97 (2): 94-102, 2005. [PubMed: 15657339]
24. Ledesma MC, Jung-Hynes B, Schmit TL, et al.: Selenium and vitamin E for prostate cancer: post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) status. Mol Med 17 (1-2): 134-43, 2011 Jan-Feb. [PMC free article: PMC3022975] [PubMed: 20882260]
25. Dunn BK, Richmond ES, Minasian LM, et al.: A nutrient approach to prostate cancer prevention: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). Nutr Cancer 62 (7): 896-918, 2010. [PubMed: 20924966]
26. Select Committee on GRAS Substances (SCOGS) Opinion: alpha-Tocopherols. Silver Spring, Md: Food and Drug Administration, 2013. Available online. Last accessed April 19, 2016.

Pomegranate, Green Tea, Broccoli, and Turmeric

In a placebo-controlled, double-blind, randomized study, 199 men with localized prostate cancer were randomly assigned to either a food supplement or placebo (2:1) for 6 months.[1] The food supplement contained 100 mg each of pomegranate whole fruit powder, broccoli powder and turmeric powder, and 20 mg of green tea extract (equivalent to 100 mg of tea). The herbal ingredients in this supplement were raw, dry, powdered plant materials that were not chemically standardized. Chemical standardization is widely performed with herbal extracts, as a means of enhancing the reproducibility of studies with herbal dietary supplements via qualitative and quantitative chemical analysis. There were no significant differences in age or Gleason score between the groups. Forty percent of the patients had rising prostate-specific antigen (PSA) levels following local therapy and 60% were on active surveillance (prelocal therapy). The study found a median rise in PSA of 14.7% after 6 months in the supplement group compared with a 78.5% median rise in PSA in the placebo group. The supplement was well tolerated with no significant increase in adverse events compared with placebo, although a trend was noted towards increased flatulence and loose bowels in the supplement group.

Important differences exist between pomegranate preparation and standardization. While dried fruit powder is commonly found in the marketplace, an equal amount of pomegranate fruit extract has a much higher content of polyphenols that are considered the bioactive constituents and can be used for the chemical standardization of preparations.

Zyflamend

References

1. Thomas R, Williams M, Sharma H, et al.: A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer--the U.K. NCRN Pomi-T study. Prostate Cancer Prostatic Dis 17 (2): 180-6, 2014. [PMC free article: PMC4020278] [PubMed: 24614693]
2. Ekmekcioglu S, Chattopadhyay C, Akar U, et al.: Zyflamend mediates therapeutic induction of autophagy to apoptosis in melanoma cells. Nutr Cancer 63 (6): 940-9, 2011. [PubMed: 21745040]
3. Bemis DL, Capodice JL, Anastasiadis AG, et al.: Zyflamend, a unique herbal preparation with nonselective COX inhibitory activity, induces apoptosis of prostate cancer cells that lack COX-2 expression. Nutr Cancer 52 (2): 202-12, 2005. [PubMed: 16201851]
4. Sandur SK, Ahn KS, Ichikawa H, et al.: Zyflamend, a polyherbal preparation, inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of NF-kappa B activation and NF-kappa B-regulated gene products. Nutr Cancer 57 (1): 78-87, 2007. [PubMed: 17516865]
5. Yan J, Xie B, Capodice JL, et al.: Zyflamend inhibits the expression and function of androgen receptor and acts synergistically with bicalutimide to inhibit prostate cancer cell growth. Prostate 72 (3): 244-52, 2012. [PubMed: 21656835]
6. Yang P, Cartwright C, Chan D, et al.: Zyflamend-mediated inhibition of human prostate cancer PC3 cell proliferation: effects on 12-LOX and Rb protein phosphorylation. Cancer Biol Ther 6 (2): 228-36, 2007. [PubMed: 17218785]
7. Huang EC, Chen G, Baek SJ, et al.: Zyflamend reduces the expression of androgen receptor in a model of castrate-resistant prostate cancer. Nutr Cancer 63 (8): 1287-96, 2011. [PubMed: 21958043]
8. Huang EC, Zhao Y, Chen G, et al.: Zyflamend, a polyherbal mixture, down regulates class I and class II histone deacetylases and increases p21 levels in castrate-resistant prostate cancer cells. BMC Complement Altern Med 14: 68, 2014. [PMC free article: PMC3938081] [PubMed: 24555771]
9. Kim JH, Park B, Gupta SC, et al.: Zyflamend sensitizes tumor cells to TRAIL-induced apoptosis through up-regulation of death receptors and down-regulation of survival proteins: role of ROS-dependent CCAAT/enhancer-binding protein-homologous protein pathway. Antioxid Redox Signal 16 (5): 413-27, 2012. [PMC free article: PMC3261028] [PubMed: 22004570]
10. Kunnumakkara AB, Sung B, Ravindran J, et al.: Zyflamend suppresses growth and sensitizes human pancreatic tumors to gemcitabine in an orthotopic mouse model through modulation of multiple targets. Int J Cancer 131 (3): E292-303, 2012. [PMC free article: PMC3288649] [PubMed: 21935918]
11. Rafailov S, Cammack S, Stone BA, et al.: The role of Zyflamend, an herbal anti-inflammatory, as a potential chemopreventive agent against prostate cancer: a case report. Integr Cancer Ther 6 (1): 74-6, 2007. [PubMed: 17351029]
12. Capodice JL, Gorroochurn P, Cammack AS, et al.: Zyflamend in men with high-grade prostatic intraepithelial neoplasia: results of a phase I clinical trial. J Soc Integr Oncol 7 (2): 43-51, 2009. [PubMed: 19476738]

Overview

Many widely available dietary supplements are marketed to support prostate health. African cherry (Pygeum africanum) and beta-sitosterol are two related supplements that have been studied as potential prostate cancer treatments.

African Cherry/P. africanum

P. africanum is a tree from the Rosaceae family that grows in tropical zones. It is found in a number of African countries including Kenya, Madagascar, Uganda, and Nigeria. Bark from the P. africanum tree was used by African tribes to treat urinary symptoms and gastric pain.[1] In the 18th century, European travelers learned from South African tribes that P. africanum was used to treat bladder discomfort and “old man’s disease” (enlarged prostate).

Since 1969, bark extracts from P. africanum have been available as prescription drugs in Europe and have been widely used to treat benign prostatic hyperplasia.[2,3] The bark contains a number of compounds including saturated and unsaturated fatty acids, phytosterols (e.g., beta-sitosterol), pentacyclic triterpenoids (e.g., oleanolic acid), alcohols, and carbohydrates. The extract is obtained by macerating and solubilizing the bark in an organic solvent. The extract is then purified from the solvent.[1]

Two components of P. africanum bark extracts, atraric acid and N-butylbenzene-sulfonamide, are androgen receptor inhibitors, as indicated by both in vitro [4-6] and animal in vivo [7] studies. This activity is produced by each of these components at concentrations that are significantly lower than the clinically achieved concentration of the antiandrogen flutamide.[8]

Beta-Sitosterol

Beta-sitosterol is a member of the phytosterol family of phytochemicals. It is found ubiquitously in plants. Pygeum africanum, saw palmetto (Serenoa repens), and some legumes can contain rather high concentrations. As a type of phytosterol (or plant sterol), beta-sitosterol has a similar structure to cholesterol. Phytosterols, including beta-sitosterol, reduce absorption of dietary cholesterol and their potential to protect against cardiovascular disease is under investigation. Mean plasma beta-sitosterol concentration in a small group of healthy male volunteers in Vienna, Austria, was 2.83 μg/mL (approximately 7 μM).[9] Interestingly, however, a rare condition caused by mutations in the adenosine triphosphate-binding cassette (ABC) transporter ABCG5 or ABCG8 genes results in an inherited sterol storage disease with markedly increased serum concentrations of plant sterols such as sitosterol and leads to premature atherosclerosis and large xanthomas.[10]

Research has also suggested that phytosterols may have anticarcinogenic properties, but the exact mechanisms are unknown.[11] Phytosterols may exert antitumor effects by acting on immune and hormonal systems, or by directly targeting cell cycles and inducing apoptosis in tumor cells.[12]

Beta-sitosterol at very high concentrations (i.e., 16 mM or 6.64 mg/mL) has been shown to significantly inhibit growth of PC-3 prostate cancer cells and induce apoptosis.[13,14] Beta-sitosterol is very poorly bioavailable, with an estimated 0.41% of dietary beta-sitosterol absorbed, and circulating blood levels of about 3 μg/mL to 9 μg/mL in individuals consuming diets containing normal to high amounts of plant-based foods (approximately 1,000 times less than the concentration used in the study).[9,15] Associated with these effects are decreasing levels of cell cycle regulators p21 and p27 in the cancer cells and an increased production of reactive oxygen species.

References

1. Brackman FG, Edgar A, Coates PM: Pygeum. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 650-5.
2. Ishani A, MacDonald R, Nelson D, et al.: Pygeum africanum for the treatment of patients with benign prostatic hyperplasia: a systematic review and quantitative meta-analysis. Am J Med 109 (8): 654-64, 2000. [PubMed: 11099686]
3. Levin RM, Das AK: A scientific basis for the therapeutic effects of Pygeum africanum and Serenoa repens. Urol Res 28 (3): 201-9, 2000. [PubMed: 10929430]
4. Papaioannou M, Schleich S, Prade I, et al.: The natural compound atraric acid is an antagonist of the human androgen receptor inhibiting cellular invasiveness and prostate cancer cell growth. J Cell Mol Med 13 (8B): 2210-23, 2009. [PMC free article: PMC6512379] [PubMed: 18627423]
5. Papaioannou M, Schleich S, Roell D, et al.: NBBS isolated from Pygeum africanum bark exhibits androgen antagonistic activity, inhibits AR nuclear translocation and prostate cancer cell growth. Invest New Drugs 28 (6): 729-43, 2010. [PubMed: 19771394]
6. Schleich S, Papaioannou M, Baniahmad A, et al.: Extracts from Pygeum africanum and other ethnobotanical species with antiandrogenic activity. Planta Med 72 (9): 807-13, 2006. [PubMed: 16783690]
7. Shenouda NS, Sakla MS, Newton LG, et al.: Phytosterol Pygeum africanum regulates prostate cancer in vitro and in vivo. Endocrine 31 (1): 72-81, 2007. [PubMed: 17709901]
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Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of nutrition and dietary supplements for reducing the risk of developing prostate cancer or for treating prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Prostate Cancer, Nutrition, and Dietary Supplements are:

• Donald I. Abrams, MD (UCSF Osher Center for Integrative Medicine)
• Nagi B. Kumar, PhD, RD, FADA (Fellow of the American Dietetic Association)
• Channing J Paller, MD (Johns Hopkins Hospital)
• Jeffrey D. White, MD (National Cancer Institute)

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Levels of Evidence

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The preferred citation for this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Prostate Cancer, Nutrition, and Dietary Supplements. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: http://www.cancer.gov/about-cancer/treatment/cam/hp/prostate-supplements-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389500]

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