Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)–Health Professional Version
Selenium
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.[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 SEPP have been observed in some tumors, while increased expression of glutathione peroxidase 2 occurs in colorectal and lung tumors.[7]
Preclinical/Animal Studies
In vitro studies
Different selenium-containing compounds have variable effects on prostate cancer cells as well as normal cells and tissues. Both naturally occurring and synthetic organic forms of selenium have been shown to decrease the growth and function of prostate cancer cells.[9] In a 2011 study, prostate cancer cells were treated with various forms of selenium; selenite and methylseleninic acid (MSeA) had the greatest cytotoxic effects.[10]
Studies have suggested that selenium nanoparticles may be less toxic to normal tissues than are other selenium compounds. One study investigated the effects of selenium nanoparticles on prostate cancer cells. The treated cells had decreased activity of the androgen receptor, which led to apoptosis and growth inhibition.[11]
Sodium selenite
In a 2010 study, prostate cancer cells treated with sodium selenite (a natural form of selenium) exhibited increased levels of p53 (a tumor suppressor). Findings also revealed that p53 may play a key role in selenium-induced apoptosis.[12]
In a second study, the prostate cancer cell line LNCaP was modified to separately overexpress each of four antioxidant enzymes. Cells from the modified cell line were then treated with sodium selenite. The cells overexpressing manganese superoxide dismutase (MnSOD) were the only ones able to suppress selenite-induced apoptosis. These findings suggest that superoxide production in mitochondria may be important in selenium-induced apoptosis occurring in prostate cancer cells and that levels of MnSOD in cancer cells may determine the effectiveness of selenium in inhibiting those cells.[13]
One study treated prostate cancer cells and benign prostatic hyperplasia (BPH) cells with sodium selenite. Growth of LNCaP cells was stimulated by noncytotoxic, low concentrations of sodium selenite; while growth inhibition occurred in PC-3 cells at these concentrations—prompting the authors to suggest that selenium may be beneficial in advanced prostate cancer—selenium supplementation may have adverse effects in hormone-sensitive prostate cancer.[14] However, the relevance of these findings to the clinical setting is unclear. These experiments used selenium concentrations of 1 to 10 µg/mL, whereas the average U.S. adult male serum selenium concentrations are about 0.125 µg/mL,[15] and prostate tissue concentrations are about 1.5 µg/g.[16]
Animal studies
A 2012 study investigated whether various forms of selenium (i.e., SeMet and selenium-enriched yeast [Se-yeast]) differentially affect biomarkers in the prostate. Elderly dogs received nutritionally adequate or supranutritional levels of selenium in the form of SeMet or Se-yeast. Both types of selenium supplementation increased selenium levels in toenails and prostate tissue to a similar degree. The different forms of selenium supplementation showed no significant differences in DNA damage, proliferation, or apoptosis in the prostate.[17]
At least one study has compared these three forms of selenium in athymic nude mice injected with human prostate cancer cells and found that MSeA was more effective in inhibiting tumor growth than was SeMet or selenite.[18] Another study investigated the effect of age on selenium chemoprevention in mice. Mice were fed selenium-depleted or selenium-containing (at nutritional or supranutritional levels) diets for 6 months or 4 weeks and were then injected with PC-3 prostate cancer cells. Adult mice that were fed selenium-containing diets exhibited fewer tumors than did adult mice fed selenium-depleted diets. In adult mice, selenium-depleted diets resulted in tumors with more necrosis and inflammation compared with selenium-containing diets. However, in young mice, tumor development and histopathology were not affected by dietary selenium.[19]
The effects of MSeA and methylselenocysteine (MSeC) have also been explored in a transgenic model of in situ murine prostate cancer development, the TRAMP mouse.[20] Treatment with MSeA and MSeC resulted in slower progression of prostatic intraepithelial neoplasia (PIN) lesions, decreased cell proliferation, and increased apoptosis compared with treatment with water. MSeA treatment also increased survival time of TRAMP mice. TRAMP mice that received MSeA treatment starting at age 10 weeks exhibited less aggressive prostate cancer than did mice that started treatment at 16 weeks, suggesting early intervention with MSeA may be more effective than later treatment. The same research group later investigated some of the cellular mechanisms responsible for the different effects of MSeA and MSeC. MSeA and MSeC were shown to affect proteins involved in different cellular pathways. MSeA mainly affected proteins related to prostate differentiation, androgen receptor signaling, protein folding, and endoplasmic reticulum-stress responses, whereas MSeC affected enzymes involved in phase II detoxification or cytoprotection.[21] One study suggested that MSeA may inhibit cell growth and increase apoptosis by inactivating PKC isoenzymes.[22]
Human Studies
Epidemiological studies
The results of epidemiological studies suggest some complexity in the association between the blood levels of selenium and the risk of acquiring prostate cancer. As part of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg study, men completed dietary questionnaires, had blood samples taken, and were monitored every 2 to 3 years for up to 10 years. The findings revealed a significantly decreased risk of prostate cancer for individuals with higher blood selenium concentrations.[23] In a prospective pilot study, prostate cancer patients had significantly lower whole blood selenium levels than did healthy males.[24] However, in a 2009 study of prostate cancer patients, men with higher plasma selenium levels were at greater risk of being diagnosed with aggressive prostate cancer.[25]
Various molecular pathways have been explored to better understand the association between blood selenium levels and the development of prostate cancer. In the EPIC-Heidelberg study, polymorphisms in the selenium-containing enzymes GPX1 and SEP15 genes were found to be associated with prostate cancer risk.[23] Another study that used DNA samples obtained from the EPIC-Heidelberg study suggested that prostate cancer risk may be associated with single nucleotide polymorphisms (SNPs) in thioredoxin reductase and selenoprotein K genes along with selenium status.[26] A 2012 study investigated associations between variants in selenoenzyme genes and risk of prostate cancer and prostate cancer–specific mortality. Among SNPs analyzed, only GPX1 rs3448 was related to overall prostate cancer risk.[27]
A retrospective analysis of prostate cancer patients and healthy controls showed an association between aggressive prostate cancer and decreased selenium and SEPP status.[28] In the Physicians' Health Study, links between SNPs in the SEPP gene (SEPP1) and prostate cancer risk and survival were examined. Two SNPs were significantly associated with prostate cancer incidence: rs11959466 was associated with increased risk, and rs13168440 was associated with decreased risk. Tumor SEPP1 mRNA expression levels were lower in men with lethal prostate cancer than in men with nonlethal prostate cancer.[29] In one study, the direction of the association between blood selenium levels and advanced prostate cancer incidence differed according to which of two polymorphisms a patient had for the gene encoding the enzyme MnSOD. For men with the alanine-alanine (AA) genotype, higher selenium levels were associated with a reduced risk of presenting with aggressive disease, whereas the opposite was seen among men with a valine (V) allele.[25]
An analysis of 4,459 men in the Health Professionals Follow-Up Study who were initially diagnosed with prostate cancer found that selenium supplementation of 140 μg or more per day after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality. The authors recommended caution in the use of selenium supplements among men with prostate cancer. Risk of prostate cancer mortality rose at all levels of selenium consumption. Men who consumed 1 to 24 μg/day, 25 to 139 μg/day, and 140 μg/day or more of supplemental selenium had a 1.18-fold (95% confidence interval [CI], 0.73–1.91), 1.33-fold (95% CI, 0.77–2.30), and 2.60-fold (95% CI, 1.44–4.70) increased prostate cancer mortality risk compared with nonusers, respectively (Ptrend = .001). The authors reported no statistically significant association between selenium supplement use and biochemical recurrence, cardiovascular disease mortality, or overall mortality.[30]
Intervention studies
Sixty adult males were randomly assigned to receive either a daily placebo or 200 µg of selenium glycinate supplements for 6 weeks. Blood samples were collected at the start and end of the study. Compared with the placebo group, men who received selenium supplements exhibited significantly increased activity of two blood selenium enzymes and significantly decreased levels of prostate-specific antigen (PSA) at the end of the study.[31]
A meta-analysis published in 2012 reviewed human studies that investigated links between selenium intake, selenium status, and prostate cancer risk. The results suggested an association between decreased prostate cancer risk and a narrow range of selenium status (plasma selenium concentrations up to 170 ng/mL and toenail selenium concentrations between 0.85 and 0.94 µg/g).[32]
In another study, prostate cancer patients were randomly assigned to receive either combination silymarin (570 mg) and selenomethionine (240 µg) supplement or placebo daily for 6 months following radical prostatectomy. While there was no change in PSA levels between the groups after 6 months, the participants receiving supplements reported improved quality of life and showed decreases in low-density lipoprotein cholesterol and total cholesterol.[33]
In one study, 140 prostate cancer patients undergoing active surveillance were randomly assigned to receive low-dose selenium (200 µg/d), high-dose selenium (800 µg/d), or placebo daily for up to 5 years. Selenium was given in the form of Se-yeast. Men receiving the high-dose selenium, and who had the highest baseline plasma selenium levels, had a higher PSA velocity than did men in the placebo group. There was not a significant effect of selenium supplements on PSA velocity in men who had lower baseline levels of selenium.[34]
In 2013, results of a phase III randomized, placebo-controlled trial investigating the effect of selenium supplementation on prostate cancer incidence in men at high risk for the disease were reported. Subjects (N = 699) were randomly assigned to receive either daily placebo or one of two doses of high–Se-yeast (200 µg/d or 400 µg/d). They were monitored every 6 months, up to 5 years. Compared with placebo, selenium supplementation had no effect on prostate cancer incidence or PSA velocity.[35] In an earlier study, men with HGPIN were randomly assigned to receive either placebo or 200 µg of selenium daily for 3 years or until prostate cancer diagnosis. The results suggested that selenium supplementation had no effect on prostate cancer risk.[36]
The Selenium and Vitamin E Cancer Prevention Trial (SELECT)
On the basis of findings from earlier studies,[8,37] the SELECT, a large multicenter clinical trial, was initiated by the National Institutes of Health in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer. SELECT was a phase III, randomized, double-blind, placebo-controlled, population-based trial.[38] More than 35,000 men, aged 50 years or older, from more than 400 study sites in the United States, Canada, and Puerto Rico, were randomly assigned to receive vitamin E (alpha-tocopherol acetate, 400 IU/d) and a placebo, selenium (L-selenomethionine, 200 µg/d) and a placebo, vitamin E and selenium, or two placebos daily for 7 to 12 years. The primary endpoint of the clinical trial was incidence of prostate cancer.[38]
Initial results of SELECT were published in 2009. There were no statistically significant differences in rates of prostate cancer in the four groups. In the vitamin E–alone group, there was a nonsignificant increase in rates of prostate cancer (P = .06); in the selenium–alone group, there was a nonsignificant increase in incidence of diabetes mellitus (P = .16). On the basis of those findings, the data and safety monitoring committee recommended that participants stop taking the study supplements.[39]
Updated results were published in 2011. When compared with the placebo group, the rate of prostate cancer detection was significantly greater in the vitamin E–alone group (P = .008) and represented a 17% increase in prostate cancer risk. There was also greater incidence of prostate cancer in men who had taken selenium than in men who took placebo, but those differences were not statistically significant.[40]
A number of explanations have been suggested, including the dose and form of vitamin E that was used in the trial as well as the specific form of selenium chosen for the study. L-selenomethionine was used in SELECT, while selenite and Se-yeast had been used in previous studies. SELECT researchers chose selenomethionine because it was the major component of Se-yeast and because selenite was not absorbed well by the body, resulting in lower selenium stores.[41] In addition, there were concerns about product consistency with high–Se-yeast.[42] However, selenomethionine is involved in general protein synthesis and can have numerous metabolites such as methylselenol, which may have antitumor properties.[43,44]
Toenail selenium concentrations were examined in two-case cohort subset studies of SELECT participants. Total selenium concentration in the absence of supplementation was not associated with prostate cancer risk. Selenium supplementation in SELECT had no effect on prostate cancer risk among men with low selenium status at baseline but increased the risk of high-grade prostate cancer in men with higher baseline selenium status by 91% (P = .007). The authors concluded that men should avoid selenium supplementation at doses exceeding recommended dietary intakes.[45] An international collaboration compiled and reanalyzed data from 15 studies that investigated the association between blood and toenail selenium concentrations and prostate cancer risk.[46] In the analysis of 6,497 men with prostate cancer and 8,107 controls, blood selenium level was not associated with the risk of total prostate cancer, but high blood selenium level was associated with a lower risk of aggressive disease. Toenail selenium concentration was inversely associated with risk of total prostate cancer (odds ratio, 0.29; 95% CI, 0.22–0.40; Ptrend < .001), including both aggressive and nonaggressive disease.
In a case-cohort analysis of 1,434 men in the SELECT who underwent analysis of SNPs in 21 genes, investigators found support for the hypothesis that genetic variation in selenium and vitamin E metabolism/transport genes may influence the risk of overall and high-grade prostate cancer and that selenium or vitamin E supplementation may modify an individual's response to those risks.[47]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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
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- 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 Abstract]
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- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Geybels MS, Hutter CM, Kwon EM, et al.: Variation in selenoenzyme genes and prostate cancer risk and survival. Prostate 73 (7): 734-42, 2013. [PUBMED Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- Kenfield SA, Van Blarigan EL, DuPre N, et al.: Selenium supplementation and prostate cancer mortality. J Natl Cancer Inst 107 (1): 360, 2015. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- Klein EA: Selenium and vitamin E cancer prevention trial. Ann N Y Acad Sci 1031: 234-41, 2004. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Klein EA, Thompson IM, 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. [PUBMED Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- Allen NE, Travis RC, Appleby PN, et al.: Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen Prospective Studies. J Natl Cancer Inst 108 (11): , 2016. [PUBMED Abstract]
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Soy
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.
- Early-phase clinical trials with isoflavones, soy, and soy products for the prevention and treatment of prostate cancer have been limited to relatively short durations of intervention and sample sizes with low statistical power. These studies targeted heterogeneous prostate cancer patient populations (in high-risk, early- and later-stage disease) and varying doses of isoflavones, soy, and soy products, and have not demonstrated evidence of reducing prostate cancer progression.
- Other trials evaluating the role of isoflavones, soy, or soy products in the management of androgen deprivation therapy (ADT) side effects have found no improvement with isoflavone treatment compared with placebo.
- 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 11th century BC, it was not until the 18th century that the soy plant reached Europe and the United States. The soybean is an incredibly versatile plant. It can be processed into a variety of products including soy milk, miso, tofu, soy flour, and soy oil.[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] Many of these isoflavones are also found in other legumes and plants, such as red clover.
Isoflavones are quickly taken up by the gut and can be detected in plasma as soon as 30 minutes after the consumption of soy products. Studies suggest that maximum levels of isoflavone plasma concentration may be achieved by 6 hours after soy product consumption.[4] Isoflavones are phytoestrogens that bind to estrogen receptors. Prostate tissue is known to express estrogen receptor beta and it has been shown that the isoflavone genistein has greater affinity for estrogen receptor beta than for estrogen receptor alpha.[5]
A link between isoflavones and prostate cancer was first observed in epidemiological studies that demonstrated a lower risk of prostate cancer in populations consuming considerable amounts of dietary soy.[6,7] Subsequent studies evaluating the role of soy in experimental models further showed anticancer properties of soy, specifically relevant to prostate carcinogenesis. These early studies have led to a few clinical trials in humans using soy food products or supplements that targeted men with varying stages of prostate cancer. Although these studies showed modulation of intermediate endpoints or surrogate biomarkers of prostate cancer progression, the results indicating beneficial effects from soy or soy products have been mixed.
Preclinical/Animal Studies
In vitro studies
Individual isoflavones
A number of laboratory studies have examined ways in which soy components affect prostate cancer cells. In one study, human prostate cancer cells and normal prostate epithelial cells were treated with either an ethanol vehicle (carrier) or isoflavones. Treatment with genistein decreased COX-2 mRNA and protein levels in cancer cells and normal epithelial cells more than did treatment with the vehicle. In addition, cells treated with genistein exhibited reduced secretion of prostaglandin E2 (PGE2) and reduced mRNA levels of the prostaglandin receptors EP4 and FP, suggesting that genistein may exert chemopreventive effects by inhibiting the synthesis of prostaglandins, which promote inflammation.[8] In another study, human prostate cancer cells were treated with genistein or daidzein. The isoflavones were shown to down regulate growth factors involved in angiogenesis (e.g., EGF and IGF-1) and the interleukin-8 gene, which is associated with cancer progression. These findings suggest that genistein and daidzein may have chemopreventive properties.[9] Both genistein and daidzein have been shown to reduce the proliferation of LNCaP and PC-3 prostate cancer cells in vitro. However, during the 72 hours of incubation, only genistein provoked effects on the dynamic phenotype and decreased invasiveness in PC-3 cells. These results imply that invasive activity is at least partially dependent on membrane fluidity and that genistein may exert its antimetastatic effects by changing the mechanical properties of prostate cancer cells. No such effects were observed for daidzein at the same dose.[10]
Combinations of isoflavones
Some experiments have compared the effects of individual isoflavones with isoflavone combinations on prostate cancer cells. In one study, human prostate cancer cells were treated with a soy extract (containing genistin, daidzin, and glycitin), genistein, or daidzein. The soy extract induced cell cycle arrest and apoptosis in prostate cancer cells to a greater degree than did treatment with the individual isoflavones. Genistein and daidzein activated apoptosis in noncancerous benign prostatic hyperplasia (BPH) cells, but the soy extract had no effect on those cells. These findings suggested that products containing a combination of active compounds (e.g., whole foods) may be more effective in preventing cancer than individual compounds.[11] Similarly, in another study, prostate cancer cells were treated with genistein, biochanin A, quercetin, doublets of those compounds (e.g., genistein + quercetin), or with all three compounds. All of the treatments resulted in decreased cell proliferation, but the greatest reductions occurred using the combination of genistein, biochanin A, and quercetin. The triple combination treatment induced more apoptosis in prostate cancer cells than did individual or doublet compound treatments. These results indicate that combining phytoestrogens may increase the effectiveness of the individual compounds.[12]
At least one study has examined the combined effect of soy isoflavones and curcumin. Human prostate cancer cells were treated with isoflavones, curcumin, or a combination of the two. Curcumin and isoflavones in combination were more effective in lowering PSA levels and expression of the androgen receptor than were curcumin or the isoflavones individually.[13]
Animal studies
Animal models of prostate cancer have been used in studies investigating the effects of soy and isoflavones on the disease. Wild-type and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control diets or diets containing genistein (250 mg genistein/kg chow). The TRAMP mice fed with genistein exhibited reduced cell proliferation in the prostate compared with TRAMP mice fed a control diet. The genistein-supplemented diet also reduced levels of ERK-1 and ERK-2 (proteins important in stimulating cell proliferation) as well as the growth factor receptors EGFR and IGF-1R in TRAMP mice, suggesting that down regulation of these proteins may be one mechanism by which genistein exerts chemopreventive effects.[14] In one study, following the appearance of spontaneous prostatic intraepithelial neoplasia lesions, TRAMP mice were fed control diets or diets supplemented with genistein (250 or 1,000 mg genistein/kg chow). Mice fed low-dose genistein exhibited more cancer cell metastasis and greater osteopontin expression than mice fed the control or the high-dose genistein diet. These results indicate that timing and dose of genistein treatment may affect prostate cancer outcomes and that genistein may exert biphasic control over prostate cancer.[15] In a study reported in 2008, athymic mice were implanted with human prostate cancer cells and fed a control or genistein-supplemented diet (100 or 250 mg genistein/kg chow). Mice that were fed genistein exhibited less cancer cell metastasis, but no change in primary tumor volume, than did mice fed a control diet. Furthermore, other data suggested that genistein inhibits metastasis by impairing cancer cell detachment.[16] In contrast, in a study reported in 2011, there were more metastases in secondary organs in genistein-treated mice than in vehicle-treated mice. In this latter study, mice were implanted with human prostate cancer xenografts and treated daily with genistein dissolved in peanut oil (80 mg genistein/kg body weight/day or 400 mg genistein/kg body weight/d) or peanut oil vehicle by gavage. In addition, there was a reduction in tumor cell apoptosis in the genistein-treated mice compared with the vehicle-treated mice. These findings suggest that genistein may stimulate metastasis in an animal model of advanced prostate cancer.[17]
Radiation therapy is commonly used in prostate cancer, but, despite this treatment, disease recurrence is common. Therefore, combining radiation with additional therapies may provide longer-lasting results. In one study, human prostate cancer cells were treated with soy isoflavones and/or radiation. Cells that were treated with both isoflavones and radiation exhibited greater decreases in cell survival and greater expression of proapoptotic molecules than cells treated with isoflavones or radiation only. Nude mice were implanted with prostate cancer cells and treated by gavage with genistein (21.5 mg/kg body weight/d), mixed isoflavones (50 mg/kg body weight/d; contained 43% genistein, 21% daidzein, and 2% glycitein) and/or radiation. Mixed isoflavones were more effective than genistein in inhibiting prostate tumor growth, and combining isoflavones with radiation resulted in the largest inhibition of tumor growth. In addition, mice given soy isoflavones in combination with radiation did not exhibit lymph node metastasis, which was seen previously in other experiments combining genistein with radiation. These preclinical findings suggest that mixed isoflavones may increase the efficacy of radiation therapy for prostate cancer.[18]
In the treatment of prostate cancer, bone health is a common concern in the setting of hormone deprivation therapy, which is associated with bone loss. Because of increased beta versus alpha estrogen receptor binding, soy-derived compounds are thought to be protective of bone. Animal studies have shown that genistein and daidzein can prevent or reduce bone loss in a manner similar to synthetic estrogen. Both isoflavones may modulate bone remodeling by targeting and regulating gene expression and may inhibit calcium urine excretion, which also helps to maintain bone density.[19,20]
Human Studies
Human studies evaluating isoflavones and soy for the prevention and treatment of prostate cancer have included epidemiological studies and early-phase trials. Several phase I-II randomized clinical studies have examined isoflavones and soy product for bioavailability, safety, and effectiveness in prostate cancer prevention or treatment.[21-23] These studies have included a wide range of subject populations, including high-risk men; prostate cancer patient populations (localized and later-stage disease); varying doses of isoflavones, soy, and soy products; and were limited to relatively short durations of observation or intervention and sample sizes with low statistical power.
Epidemiologic studies
In 2018, a meta-analysis of studies that investigated soy food consumption and risk of prostate cancer was reported. The results of this meta-analysis suggested that high consumption of nonfermented soy foods (e.g., tofu and soybean milk) was significantly associated with a decrease in the risk of prostate cancer. Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with a reduced risk of prostate cancer.[24] However, these data from population studies must be interpreted with caution as the studies relied on self-reported data obtained using varying forms of dietary data collection instruments with recall bias, in addition to numerous forms of individual or multiple isoflavones, soy supplements, and soy foods. Additionally, these studies failed to account for other confounding genetic or behavioral variables that may affect the risk of prostate cancer.
Prevention studies
Too few randomized placebo-controlled trials have been completed to evaluate the effect of isoflavones or soy in preventing prostate cancer progression (refer to Table 3). The studies targeted men with negative prostate biopsies and elevated serum prostate-specific antigen (PSA) (2.5–10 mcg/mL at baseline). The duration of intervention was between 6 months [13] and 1 year [25,26], with varying formulations of isoflavones derived from soy [13,25] and red clover.[26] In a single trial that showed no significant changes in serum PSA after intervention with isoflavones, a reduction in prostate cancer progression at 1 year in a subgroup of men older than 65 years was demonstrated. Other than mild to moderate adverse events, no treatment-related toxicities were observed in all three trials.
Treatment of prostate cancer
Clinical trials evaluating isoflavones, soy supplements, and soy products (refer to Table 4 and Table 5) for treating localized prostate cancer before radical prostatectomy have used window-of-opportunity trial designs (from biopsy to prostatectomy). These trials have primarily focused on evaluating serum and tissue biomarkers implicated in prostate cancer progression, bioavailability in plasma and prostate tissue, and toxicity at various doses. The trials are small in size and of short duration. They are useful for informing the design of well-powered larger clinical trials in the future, but they provide inadequate data to inform clinical practice.
Isoflavones
Soy protein or whole soy products
Isoflavones and soy products for biochemical recurrence after treatment
Other studies have examined the role of isoflavones and soy products in prostate cancer patients with biochemical recurrence after treatment. However, these early-phase studies have not demonstrated any significant changes in serum PSA or PSA-doubling time, [38-41] with one study suggesting modulation of systemic soluble and cellular biomarkers consistent with limiting inflammation and suppression of myeloid-derived suppressor cells [41] (refer to Table 6).
Management of androgen deprivation therapy side-effects
ADT is commonly used for locally advanced and metastatic prostate cancer. However, this treatment is associated with a number of adverse side effects including sexual dysfunction, decreased quality of life, changes in cognition, and metabolic syndrome. Three studies have examined men undergoing ADT who were randomly assigned to receive a placebo or an isoflavone supplement (soy protein powder mixed with beverages; isoflavones, 160 mg/d) for 12 weeks. Two studies assessed ADT side effects. Neither study found an improvement in side effects following isoflavone treatment, compared with placebo.[42,43]
The third randomized placebo-controlled trial assessed changes in PSA level and biomarkers of energy metabolism (e.g., blood glucose level) and inflammation (e.g., blood interleukin-6 level). In this study of men undergoing ADT, participants were randomly assigned to receive high-dose isoflavone supplements (providing 160 mg/d total isoflavones, and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein) or a placebo for 12 weeks. The results showed no difference between the two groups in PSA levels or in levels of metabolic and inflammatory parameters (e.g., glucose, interleukin-6).[36]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Adverse Effects
References
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Vitamin D
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 fatty fish, fish liver oil, eggs, and fortified dairy products. Vitamin D is made naturally by the body when exposed to sunlight.
In 1922, researchers discovered that heated, oxidized cod-liver oil, called fat-soluble factor A and later known as vitamin D, played an important role in curing rickets in rats.[1]
Vitamin D performs many roles in the body, including the following:
- Promotes absorption of calcium in the small intestine.
- Improves muscle strength and immune function.
- Helps to reduce inflammation.
- Helps 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
In vitro studies
To study the role of vitamin D in cancer cell adhesion to endothelium, one study developed a microtube system that simulates the microvasculature of bone marrow. The study reported that 1,25-alpha-dihydroxyvitamin D3 (1,25-D3) suppressed adhesion of prostate cancer cells in the microtube system. In addition, it was shown that 1,25-D3 increased E-cadherin expression, which may prevent prostate cancer cell adhesion to endothelium by promoting cancer cell aggregation.[3]
Vitamin D–binding protein (VDBP) transports vitamin D in the bloodstream. Studies have shown that one of its products, VDBP-macrophage activating factor (VDBP-maf), may have antiangiogenic and antitumor activities. One study examined the effects of VDBP-maf on prostate cancer cells. Treating prostate cancer cells with VDBP-maf resulted in inhibited cellular migration, proliferation, and reduced levels of urokinase plasminogen activator receptor (uPAR; activity of this receptor correlates with tumor metastasis). These findings suggest that VDBP-maf has a direct effect on prostate cancer cells.[4]
Studies have reported that 1,25-D3 may play an important role in prostate cancer biology. Studies have suggested that a newly discovered protein, protein disulfide isomerase family A, member 3 (PDIA3), may function as a membrane receptor binding to 1,25-D3. According to one study, PDIA3 is expressed in normal prostate cells as well as in LNCaP and PC-3 prostate cancer cell lines. In addition, their findings suggest that 1,25-D3 may act on prostate cancer cells via multiple signaling pathways, indicating there may be a number of potential therapeutic targets.[5]
Vitamin D has also been combined with radiation in an in vitro study. In this study, prostate cancer cells were treated with valproic acid (VPA) and/or 1,25-D3, followed by radiation. Cells that were treated with VPA and/or 1,25-D3 and radiation had greater decreases in cell proliferation than did cells treated solely with radiation. The greatest reduction in cell proliferation occurred in cells treated with VPA, 1,25-D3, and radiation.[6]
In vivo studies
Tumor progression was compared in two murine models of prostate cancer. In vitamin D receptor- knockout animals, rate of tumor progression and cellular proliferation were greater than in wild type animals. However, in mice that were supplemented with testosterone, these differences did not occur, suggesting that there may be significant interaction between androgen signaling and vitamin D signaling.[7]
In a 2011 study, nude mice were fed a control diet or a diet deficient in vitamin D and were then injected with prostate cancer cells into bone marrow or into soft tissues. Osteolytic lesions were larger and progressed at a faster rate in vitamin D–deficient mice that had bone marrow injected with cancer cells than in mice that had adequate levels of vitamin D. However, there was no difference in soft tissue tumors among mice with different vitamin D levels. Results of this study show that vitamin D deficiency is associated with growth of prostate cancer cells in bone but not in soft tissue.[8]
A 2014 study evaluated calcitriol and a less-calcemic vitamin D analog in an aggressive transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Neither vitamin D analog impacted the rate of development of castration-resistant prostate cancer in mice, whether they were treated before or after castration. However, both vitamin D analogs slowed progression of primary tumors in hormone-intact mice but enhanced distant organ metastases after prolonged treatment. In sum, intervention with potent vitamin D compounds in TRAMP mice slowed androgen-stimulated tumor progression but, over time, may have led to more aggressive disease as indicated by increased distant metastases (P = .0823).[9] This preclinical data supports findings of the 2008 retrospective study [10] of an association between serum vitamin D levels and aggressive prostate cancer (refer to the Human Studies section in the Vitamin D section of this summary for more information about this study).
Vitamin D as adjuvant therapy
Cryotherapy may be used for treating prostate cancer. Studies have been conducted to identify potential agents that may help improve efficacy of the freezing procedure. In a 2010 study, mice were injected with prostate cancer cells and treated with calcitriol, cryoablation, or both. The combination treatment group experienced larger necrotic areas, more apoptosis, and less cell proliferation than did the other experimental groups.[11] A subsequent study corroborated these findings, showing that combining calcitriol and cryoablation resulted in more cell death than cryotherapy alone.[12]
Human Studies
Epidemiological studies
The relationship between vitamin D and prostate cancer has been examined in numerous epidemiological studies. Vitamin D levels were analyzed annually for 5 years in patients with nonmetastatic prostate cancer. Results showed that throughout the course of the study, vitamin D insufficiency was prevalent among these cancer patients.[13] Levels of vitamin D metabolites in prostate cancer patients were examined in a 2011 study. Analysis revealed that patients with the lowest concentrations of prediagnostic plasma 25-hydroxy vitamin D [25(OH)D] levels had a higher risk of developing metastatic prostate cancer than did patients with higher levels of 25(OH)D. However, there was no association between metastatic prostate cancer and circulating levels of 1,25(OH)D.[14] In another study, serum levels of 25(OH)D in prostate cancer patients were assessed. Results suggest that medium or high levels of serum 25(OH)D may be associated with better prognoses than lower levels of serum 25(OH)D. These findings indicate that 25(OH)D may play a role in disease progression and may be a marker of prognosis in prostate cancer patients.[15] Participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study who had been diagnosed with prostate cancer and control participants were selected for analysis and monitored for up to 20 years. Results suggested that men with a higher vitamin D status (assessed via serum 25(OH)D concentrations) had a greater risk of developing prostate cancer than did men with lower vitamin D status.[16] A 2008 retrospective study of 749 men with prostate cancer diagnosed 1 to 8 years after blood draw and 781 matched controls found higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease.[10] Both of these studies [10,16] were included in a meta-analysis of 21 studies, involving 11,941 cases and 13,870 controls, that found a 17% elevated risk of prostate cancer in men with higher levels of 25(OH)D.[17] One explanation offered for this finding may be a potential detection bias with men from higher socio-economic groups who have higher vitamin D levels and who are more likely to undergo prostate-specific antigen (PSA) testing, resulting in higher reported incidence rates.
In one case-control study of men who had undergone prostate biopsies, men who had lower vitamin D levels before biopsy were more likely to have cancer detected at biopsy than did men whose prebiopsy vitamin D levels were not lower.[18] Serum 25(OH)D levels were obtained from 667 men in Chicago undergoing first prostate biopsy for an elevated PSA or an abnormal digital rectal exam.[18] Severe vitamin D deficiency (<12 ng/mL) was associated with increased risk of a prostate cancer diagnosis on biopsy among African American men. Severe deficiency was positively associated with higher Gleason score (≥4+4), higher clinical stage (>cT2b), and overall risk category in both white American and African American men. In contrast, baseline serum 25(OH)D levels obtained in a case (n = 1,731)–cohort (n = 3,203) analysis from the Selenium and Vitamin E Cancer Prevention Trial found significantly reduced risks among men who had moderate concentrations (45–70 nmol/L) compared with men who had lower or higher values.[19] This U-shaped association was most pronounced for cancers with Gleason scores of 7 to 10. One hundred ninety men who participated in a large epidemiologic study underwent radical prostatectomy for clinically localized prostate cancer.[20] At the time of prostatectomy, 87 men (45.8%) exhibited adverse pathology, defined as primary Gleason 4, any Gleason 5 or extraprostatic extension. Men with adverse pathology had lower median serum 25(OH)D (22.7 ng/mL), compared with their counterparts (27.0 ng/mL), and were also more likely to have a serum 25(OH)D level less than 30 ng/mL.
An important means of obtaining vitamin D is via sunlight. Studies have investigated the potential link between sunlight exposure and prostate cancer. According to a 2006 study, PSA levels rise at a slower rate during spring and summer than at other times of the year; this may be related to higher vitamin D levels obtained during those months.[21] One study found that while men with low levels of sun exposure had increased risk of all prostate cancers, among men with prostate cancer, less sun exposure was associated with lower risk of advanced disease. Results of a meta-analysis, published in the same report, showed that men with low sun exposure had an increased risk of incident and advanced prostate cancer.[22] Analysis of mortality rate data from 1950 to 1994 revealed that the geographic distribution of prostate cancer mortality in the United States is inversely related to UV radiation. In addition, this relationship is more evident in areas north of 40 degrees N latitude.[23] Likewise, a study in France reported that UV radiation may be associated with reductions in cancer risk and mortality.[24]
A number of studies have explored a possible connection between the vitamin D receptor (VDR) and risk of prostate cancer. A 2011 prospective study examined VDR expression in prostate tumors. Patients with high levels of VDR expression had lower PSA at diagnosis, less advanced tumor stage, and reduced risk of lethal prostate cancer compared with patients with lower levels of VDR expression in tumors.[25] In a 2009 study, genetic variants in VDR were analyzed in prostate cancer patients participating in the Prostate Testing for Cancer and Treatment (ProtecT) trial. Five polymorphisms of VDR were identified in the participants. A meta-analysis, published in the same report, revealed no association between specific variants and prostate cancer stage (TNM staging system), but found that three genotypes (BSML, APAL, and TAQL) may be associated with cancer grade (Gleason score), suggesting there may be a link between specific VDR polymorphisms and advanced prostate cancer at diagnosis.[26] Polymorphisms in the VDR receptor, the vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1) were examined in a 2010 study. Variations in the three genes investigated were associated with changes in risk of recurrence and progression of prostate cancer as well as prostate cancer mortality.[27] A case-control study analyzed the correlation between VDBP single nucleotide polymorphisms (SNPs) and prostate cancer risk. Two SNPs in VDBP were associated with increased prostate cancer risk and high Gleason grade.[28] However in another large cohort-consortium study, statistically significant association was not observed for either 25(OH)D or vitamin D-related SNPs with fatal prostate cancer.[29]
A 2008 meta-analysis of 45 observational studies found no association between intake of vitamin D and prostate cancer risk.[30] A meta-analysis published in 2011 reviewed 25 studies examining the link between prostate cancer incidence and indicators of vitamin D. Analysis of those studies found no association between dietary vitamin D or circulating concentrations of vitamin D and risk of prostate cancer.[31] However, in a cross-sectional analysis of 119 men (88 African American and 31 European American men) undergoing prostatectomy, tumor proliferation as indicated by Ki-67 measured in prostate tissue demonstrated an inverse correlation between serum 1,25(OH)D and Ki-67 in tumor cells, providing early evidence of antiproliferative property of vitamin D. No correlation was observed between 25(OH)D and biomarker of tumor proliferation (Ki-67).[32]
Intervention studies
Calcitriol, the hormonally active form of vitamin D, has been the focus of some studies in prostate cancer patients. In an open-label, phase II study, patients with recurrent prostate cancer were treated with calcitriol and naproxen for 1 year. The combination of calcitriol and naproxen was effective in decreasing the rate of rising PSA levels in study participants, suggesting it may slow disease progression.[33] In a 2010 study, patients with castration-resistant prostate cancer were treated with calcitriol and dexamethasone. The results indicated that while the treatments were well tolerated, they did not have an effect on participants' PSA levels.[34]
In a 2009 study, patients with locally advanced or metastatic prostate cancer and asymptomatic progression of their PSA levels were treated with vitamin D2 (ergocalciferol) at either 10 μg or 25 μg daily. The investigators reported that about 20% of these patients had at least a 25% drop in PSA level 3 months after initiating the vitamin D2.[35]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Adverse Effects
Vitamin D toxicity
In most cases, symptoms of vitamin D toxicity are caused by hypercalcemia, but limited evidence suggests high concentrations of vitamin D may also be expressed in various organs, including the kidneys, bones, central nervous system, and cardiovascular system. Symptoms of toxicity may be observed at an intake of 10,000 to 50,000 IU per day over a period of many years. Hypercalcemia results from the vitamin D–dependent increase in intestinal absorption of calcium, leading to rapid increases in blood calcium levels. Side effects include loss of the urinary concentrating mechanism of the kidney tubule (resulting in polyuria and polydipsia), decrease in growth factor receptor, hypercalciuria, and the metastatic calcification of soft tissues. The central nervous system may also be affected, resulting in severe depression and anorexia.[36]
A systematic review of the interactions and pharmacokinetics of vitamin D and drugs used for the treatment of cancer was published.[37] Based on the review, 26 articles met the inclusion criteria. Calcitriol was the most commonly administered form of vitamin D, and adults with prostate cancer and solid tumors were the most well-represented populations in this systematic review. Hypercalcemia (at a dose of 74 μg/wk [3,000 IU]; 125 μg/wk [5,000 IU] with the addition of dexamethasone) was the most frequently reported side effect. Hypophosphatemia was also observed in two studies [38,39] that administered vitamin D in conjunction with docetaxel in men with prostate cancer. The authors concluded that no adverse effects were experienced beyond what was expected from high-dose calcitriol supplementation and was denoted as having a low risk of interaction. Some chemotherapeutic regimens appear to reduce serum 25(OH)-D3 and/or 1,25-D3.
A number of studies evaluated the safety and efficacy of high-dose calcitriol in conjunction with chemotherapy drugs in men with androgen-independent prostate cancer, hormone-refractory prostate cancer, and metastatic castration-resistant prostate cancer.[39-41] In the studies utilizing docetaxel plus calcitriol for men with androgen-independent prostate cancer, no increased toxicity was observed when compared with docetaxel alone.
In men with hormone-refractory prostate cancer, one study examined the activity and tolerability of weekly high-dose calcitriol (32 μg/wk [1,300 IU]) with docetaxel in patients who had previously received docetaxel treatment.[38] Calcitriol was given orally in three divided doses, and docetaxel was given intravenously (30 mg/m2) with dexamethasone (8 mg) orally 12 hours before, at the time of, and 12 hours after docetaxel administration. Most of the side effects were expected toxicities related to the chemotherapy. Grade 2 hypercalcemia was observed in one patient. Administration of calcitriol was discontinued until hypercalcemia resolved. Supplementation was restarted after two weeks. In another patient, persistent grade 3 fatigue was observed, and treatment of calcitriol was discontinued as docetaxel was reduced.
Phase I trials
Phase I studies have looked at the maximum tolerated dose (MTD) of weekly intravenous and oral calcitriol in conjunction with various chemotherapy drugs for cancer treatment. One study examined the MTD of calcitriol in conjunction with gefitinib at 250 mg/day (oral chemotherapy used to treat lung cancer) in 32 patients with advanced solid tumors that were metastatic or unresectable.[42] At doses up to 74 μg (3,000 IU) per week, no dose-limiting toxicities were observed. Grade 2 hypercalcemia was observed in two of four patients receiving 96 μg per week (3,900 IU) of calcitriol and was denoted nontolerable. No significant bone marrow suppression was observed at any dose. A dose of 74 μg (3,000 IU) per week was denoted as the MTD. The study suggests no major interaction between calcitriol and gefitinib.
A second phase I study examined the MTD and pharmacokinetics of calcitriol when administered with paclitaxel over the course of 6 weeks.[43] Thirty-six patients (heterogenous diagnoses) were enrolled in the trial and received escalating doses of oral calcitriol starting at 4 μg (160 IU) for 3 consecutive days, and increasing to 38 μg (1,520 IU) with an 80-mg/m2 infusion of paclitaxel given weekly. Results demonstrate that very high doses of calcitriol can be safely administered with paclitaxel. There was no dose-limiting toxicity in the trial, and at a dose of 38 μg/wk, no clinically significant hypercalcemia occurred. However, it is important to note that participants were administered from 8 to 76 capsules of calcitriol with no report of adherence to the prescribed dose of calcitriol.
References
- Wolf G: The discovery of vitamin D: the contribution of Adolf Windaus. J Nutr 134 (6): 1299-302, 2004. [PUBMED Abstract]
- 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 September 13, 2017.
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- Zheng Y, Zhou H, Ooi LL, et al.: Vitamin D deficiency promotes prostate cancer growth in bone. Prostate 71 (9): 1012-21, 2011. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- Murphy AB, Nyame Y, Martin IK, et al.: Vitamin D deficiency predicts prostate biopsy outcomes. Clin Cancer Res 20 (9): 2289-99, 2014. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Nyame YA, Murphy AB, Bowen DK, et al.: Associations Between Serum Vitamin D and Adverse Pathology in Men Undergoing Radical Prostatectomy. J Clin Oncol 34 (12): 1345-9, 2016. [PUBMED Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- Holt SK, Kwon EM, Koopmeiners JS, et al.: Vitamin D pathway gene variants and prostate cancer prognosis. Prostate 70 (13): 1448-60, 2010. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- Rosenberg A, Nettey OS, Gogana P, et al.: Physiologic serum 1,25 dihydroxyvitamin D is inversely associated with prostatic Ki67 staining in a diverse sample of radical prostatectomy patients. Cancer Causes Control 30 (2): 207-214, 2019. [PUBMED Abstract]
- Srinivas S, Feldman D: A phase II trial of calcitriol and naproxen in recurrent prostate cancer. Anticancer Res 29 (9): 3605-10, 2009. [PUBMED Abstract]
- 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 Abstract]
- Newsom-Davis TE, Kenny LM, Ngan S, et al.: The promiscuous receptor. BJU Int 104 (9): 1204-7, 2009. [PUBMED Abstract]
- 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 September 13, 2017.
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
Vitamin E
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 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
Epidemiologic studies
The National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study was initiated to examine whether supplemental vitamin E and dietary tocopherol intakes may prevent prostate cancer. Participants in the study completed food-frequency questionnaires and were monitored for 5 years. No association between vitamin E supplements and prostate cancer risk was found. However, a reduction in the risk of advanced prostate cancer was observed with high intakes of gamma-tocopherol.[6]
In a 2010 study, levels of trace elements and vitamin E were measured in prostate cancer patients. Prostate cancer patients had significantly lower levels of plasma vitamin E than did healthy controls. In addition, there was an inverse association between prostate-specific antigen levels and plasma vitamin E.[7]
Studies suggest that alpha-tocopherol–associated protein (TAP) may have capabilities as a tumor suppressor in prostate cancer. In a 2007 study, prostate cancer specimens, which had been obtained from radical prostatectomy, were examined for TAP expression. Results showed reduced TAP expression in prostate cancer tissue and lower levels of TAP were associated with higher clinical stage and larger tumor size.[8]
A study published in 2011 examined serum alpha-tocopherol and supplemental vitamin E intake with sex steroid hormones in participants in the Third National Health and Nutrition Examination Survey (NHANES III). Results showed an inverse association between serum alpha-tocopherol levels and sex steroid hormones, but only in smokers.[9]
Serum alpha-tocopherol and gamma-tocopherol levels and prostate cancer risk were examined in participants in the Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial. An inverse relationship was observed between alpha-tocopherol levels and prostate cancer, but only in current and recently former smokers.[10] A meta-analysis of nine nested case-control studies, representing approximately 370,000 men from several countries, also found an inverse relationship between blood alpha-tocopherol levels and prostate cancer risk, but in all patients studied rather than limited to a smoking subset.[11] No association was seen with gamma-tocopherol levels in this analysis. The risk of prostate cancer decreased by 21% for every 25 mg/L increase in blood alpha-tocopherol levels.
The North Carolina-Louisiana Prostate Cancer Project investigated racial and geographic differences in prostate cancer aggressiveness.[12] The effects of food intake of tocopherols, vitamin E supplementation, and adipose tissue biomarkers of tocopherol were studied. In 1,023 African American men and 1,079 white men studied with incident prostate cancer, inverse associations were observed between dietary sources of tocopherol and prostate cancer aggressiveness that were statistically significant in white men but not in African American men.
Intervention Studies
The Physicians’ Health Study II investigated whether vitamin C or vitamin E prevents prostate cancer and other cancers in men. Participants in the study were randomly assigned to receive vitamin E (synthetic alpha-tocopherol, 400 IU qod) and/or vitamin C (synthetic ascorbic acid, 500 mg/d) supplements and were monitored for an average of 8 years. The overall rates of prostate cancer were very similar in the vitamin E supplement and placebo groups, suggesting that vitamin E may not prevent prostate cancer. Furthermore, vitamin E did not have an effect on total cancer or mortality in these participants.[13]
Although not primarily designed for this purpose, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study has been a resource for researchers investigating prostate cancer and vitamin E.[14] A long follow-up study of participants in the ATBC Study was conducted. Baseline serum alpha-tocopherol levels and dietary intake of vitamin E had been assessed and participants were monitored for up to 19 years. Findings revealed that while there was no association between dietary vitamin E levels and prostate cancer risk, higher serum alpha-tocopherol levels may be associated with a decreased risk for developing advanced prostate cancer.[15] In a 2009 study, blood samples obtained from participants in the ATBC Study were analyzed and genotyped. Results showed that genetic variations in the TTPA and SEC14L2 genes were associated with serum alpha-tocopherol but did not directly affect prostate cancer risk. However, results suggested that polymorphisms in SEC14L2 may influence the effect of alpha-tocopherol supplementation on prostate cancer risk.[16] One study also focused on the ATBC Study and investigated whether serum alpha-tocopherol levels affected survival time in men diagnosed with prostate cancer. Serum alpha-tocopherol levels were assessed at baseline and 3 years later. Higher serum alpha-tocopherol levels, at both baseline and the 3-year point, were associated with improved prostate cancer survival.[17]
A 2011 study examined links between serum alpha- and gamma-tocopherols and risk of prostate cancer among participants in the Carotene and Retinol Efficacy Trial (CARET). CARET was a randomized, placebo-controlled study that investigated whether daily supplementation of beta-carotene and retinyl palmitate would reduce the risk of lung cancer in heavy smokers and asbestos-exposed workers. Results indicated that among current smokers, higher levels of serum alpha- and gamma-tocopherols were associated with reduced risk of aggressive prostate cancer. In addition, findings suggested there may be an interaction between myeloperoxidase (MGO) G-463A genotype, serum alpha-tocopherol level, and prostate cancer risk. Specific genotypes were associated with increased prostate cancer risk in subjects with low levels of serum alpha-tocopherol, while those same genotypes along with higher levels of alpha-tocopherol were associated with reduced risk of prostate cancer.[18]
The Selenium and Vitamin E Cancer Prevention Trial (SELECT)
On the basis of findings from earlier studies,[14,19] the SELECT, a large multicenter clinical trial, was initiated by the NIH in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer. SELECT was a phase III, randomized, double-blind, placebo-controlled, population-based trial.[20] More than 35,000 men, aged 50 years or older, from more than 400 study sites in the United States, Canada, and Puerto Rico were randomly assigned to receive vitamin E (all-rac-alpha-tocopherol acetate, 400 IU/d) and a placebo, selenium (L-selenomethionine, 200 µg/d) and a placebo, vitamin E and selenium, or two placebos daily for 7 to 12 years. The primary endpoint of the clinical trial was incidence of prostate cancer.[20]
Initial results of SELECT were published in 2009. There were no statistically significant differences in rates of prostate cancer in the four groups. In the vitamin E–alone group, there was a nonsignificant increase in rates of prostate cancer (P = .06); in the selenium–alone group, there was a nonsignificant increase in incidence of diabetes mellitus (P = .16). On the basis of those findings, the data and safety monitoring committee recommended that participants stop taking the study supplements.[21]
Updated results were published in 2011. When compared with placebo, the rate of prostate cancer detection was significantly greater in the vitamin E–alone group (P = .008) and represented a 17% increase in prostate cancer risk. There was also greater incidence of prostate cancer in men who had taken selenium than in men who had taken placebo, but those differences were not statistically significant.[22]
Toenail selenium levels were assayed in a two-case cohort study of a subset of SELECT participants. Vitamin E supplementation (alone) had no effect among men with high selenium status at baseline but increased the risks of total (63%; P = .02), low-grade (46%; P = .09), and high-grade (111%; P = .008) prostate cancer among men with lower baseline selenium status. The authors concluded that men older than 55 years should avoid supplementation with either vitamin E or selenium at doses exceeding dietary recommendations.[23] In a case-cohort analysis of 1,434 men in the SELECT who underwent analysis of single nucleotide polymorphisms in 21 genes, investigators found support for the hypothesis that genetic variation in selenium and vitamin E metabolism/transport genes may influence the risk of overall- and high-grade prostate cancer and that selenium or vitamin E supplementation may modify an individual's response to those risks.[24]
The dose and form of vitamin E used in SELECT may have contributed to the results. On the basis of the results of the ATBC Study, all-rac-alpha-tocopheryl acetate was the form of vitamin E used in SELECT. The dose used in SELECT (400 IU) was higher than that in the ATBC Study. SELECT researchers opted for the higher dose because it was found in vitamin supplements, there was evidence for benefits of higher doses (including reductions in Alzheimer’s disease and age-related macular degeneration), and it was thought the higher dose would be more protective against prostate cancer than a lower dose.[25] Following the results of SELECT, it has been posited that high levels of alpha-tocopherol may affect levels of gamma-tocopherol, another form of vitamin E that may have chemopreventive effects.[26] Another important difference between the ATBC Study and SELECT that may explain the findings was the smoking status of study participants. Participants in the ATBC Study were smokers, while 7.5% of SELECT participants used tobacco products.[27]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Adverse Effects
Alpha-tocopherols have been deemed Generally Recognized as Safe by the U.S. Food and Drug Administration.[28]
In the Physicians’ Health Study II, there were no significant adverse effects reported for gastrointestinal tract symptoms, fatigue, drowsiness, skin discoloration or rashes, or migraine. However, participants who took vitamin E (alpha-tocopherol, 400 IU qod) experienced a greater number of hemorrhagic strokes than did participants who took placebo.[13] An increase in hemorrhagic strokes among participants in the vitamin E group (alpha-tocopherol, 50 mg/d) also was noted in the ATBC Study.[14]
In the initial report of results from SELECT, there were no significant differences between incidences of less severe adverse effects (e.g., alopecia, dermatitis, and nausea) experienced by the groups that received vitamin E (rac-alpha-tocopheryl acetate, 400 IU/d) and those experienced by the other treatment groups.[21] Follow-up analysis of SELECT participants revealed an increased risk of prostate cancer among men in the vitamin E–alone group.[22]
References
- Pekmezci D: Vitamin E and immunity. Vitam Horm 86: 179-215, 2011. [PUBMED Abstract]
- 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 Abstract]
- Ni J, Yeh S: The roles of alpha-vitamin E and its analogues in prostate cancer. Vitam Horm 76: 493-518, 2007. [PUBMED Abstract]
- Mustacich DJ, Bruno RS, Traber MG: Vitamin E. Vitam Horm 76: 1-21, 2007. [PUBMED Abstract]
- 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.
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Antwi SO, Steck SE, Su LJ, et al.: Dietary, supplement, and adipose tissue tocopherol levels in relation to prostate cancer aggressiveness among African and European Americans: The North Carolina-Louisiana Prostate Cancer Project (PCaP). Prostate 75 (13): 1419-35, 2015. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Clark LC, Combs GF, 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 Abstract]
- Klein EA: Selenium and vitamin E cancer prevention trial. Ann N Y Acad Sci 1031: 234-41, 2004. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Klein EA, Thompson IM, 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Chan JM, Darke AK, Penney KL, et al.: Selenium- or Vitamin E-Related Gene Variants, Interaction with Supplementation, and Risk of High-Grade Prostate Cancer in SELECT. Cancer Epidemiol Biomarkers Prev 25 (7): 1050-1058, 2016. [PUBMED Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- Select Committee on GRAS Substances (SCOGS) Opinion: alpha-Tocopherols. Silver Spring, Md: Food and Drug Administration, 2013. Available online. Last accessed September 13, 2017.
Multicomponent Therapies
Pomi-T (Pomegranate, Green Tea, Broccoli, and Turmeric)
In a placebo-controlled, double-blind, randomized study, 199 men with localized prostate cancer were randomly assigned to either a food supplement, Pomi-T, or placebo (2:1) for 6 months.[1] Pomi-T contained 100 mg each of pomegranate whole fruit powder, broccoli powder, and turmeric powder; and 20 mg of green tea extract (equivalent to 100 mg of tea). The herbal ingredients in this supplement were raw, dry, powdered plant materials and one plant extract, none of which were chemically standardized. Chemical standardization is widely performed with herbal extracts, as a means of enhancing the reproducibility of studies with herbal dietary supplements via qualitative and quantitative chemical analysis. There were no significant differences in age or Gleason score between the groups. Forty percent of the patients had rising prostate-specific antigen (PSA) levels following local therapy and 60% were on active surveillance (prelocal therapy). The study found a median rise in PSA of 14.7% after 6 months in the Pomi-T group compared with a 78.5% median rise in PSA in the placebo group. The supplement was well tolerated with no significant increase in adverse events compared with placebo, although a trend was noted towards increased flatulence and loose bowels in the supplement group.
Important differences exist between pomegranate preparation and standardization. While dried fruit powder is commonly found in the marketplace, an equal amount of pomegranate fruit extract has a much higher content of polyphenols that are considered the bioactive constituents and can be used for the chemical standardization of preparations.
Lycopene, Selenium, and Green Tea
In a randomized, double-blinded, placebo-controlled study of a supplement containing lycopene (35 mg), selenium (55 µg), and green tea catechins (600 mg) that was given for 6 months and targeted men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation, a higher incidence of prostate cancer was seen on rebiopsy in men who received the supplement. Although the expected (or historical) rate of progression to prostate cancer is less than 20% (even at 1 year), more than 25.5% of this population of men had a diagnosis of prostate cancer at 6 months, which may be attributed to inadequate sampling and potentially missed cancers at baseline. A high percentage of positive biopsies raises the concern for cancers missed on baseline biopsy, and thus, further study is warranted.[2]
Lycopene and Other Components
One study randomly assigned 79 men before prostatectomy to a nutritional intervention with tomato products containing 30 mg of lycopene daily; tomato products plus selenium, omega-3 fatty acids, soy isoflavones, grape/pomegranate juice, and green/black tea; or a control diet for 3 weeks.[3] There were no differences in PSA values between the intervention and control groups. However, a post hoc exploratory analysis found lower PSA values in men with intermediate-risk prostate cancer who consumed the tomato products and in men with the highest increases in lycopene levels.
Zyflamend
Overview
- Zyflamend is a dietary supplement that contains supercritical fluid (CO2) and hydroalcoholic extracts of the following herbs, combined and suspended in olive oil: rosemary, turmeric, ginger, holy basil, green tea, hu zhang, Chinese goldthread, barberry, oregano, and Baikal skullcap.
- The individual components of Zyflamend have anti-inflammatory and possible anticarcinogenic properties.
- In various preclinical studies, Zyflamend has been shown to suppress the expression of certain genes involved in the inflammatory response and in cancer progression, such as cyclooxygenase 1(COX-1), COX-2, 5-lipoxygenase (5-LOX), and 12-LOX.
- In other preclinical studies, Zyflamend demonstrated single-agent anticancer activity, and it improved cancer suppression when used with hormonal and chemotherapy agents.
- Results of a phase I study of Zyflamend suggest that use of this supplement is not associated with serious toxicity or adverse effects.
General information and history
Zyflamend is a dietary supplement that contains supercritical fluid (CO2) and hydroalcoholic extracts of the following herbs, combined and suspended in olive oil:
- Rosemary (Rosmarinus officinalis L.).
- Turmeric (Curcuma longa L.).
- Ginger (Zingiber officinale Roscoe).
- Holy basil (Ocimum sanctum L.).
- Green tea (Camellia sinensis [L.] Kuntze).
- Hu zhang (Polygonum cuspidatum Siebold & Zucc.).
- Chinese goldthread (Coptis chinensis Franch.).
- Barberry (Berberis vulgaris L.).
- Oregano (Origanum vulgare L.).
- Baikal skullcap (Scutellaria baicalensis Georgi).
The individual components of Zyflamend have anti-inflammatory and possible anticarcinogenic properties. For example, results of a 2011 study suggest that Zyflamend may inhibit the growth of melanoma cells.[4]
The extracts in Zyflamend have been shown to have anti-inflammatory effects via inhibition of cyclooxygenase (COX) activity. COXs are enzymes that convert arachidonic acid into prostaglandins, which are thought to play a role in tumor development and metastasis. One COX enzyme, COX-2, is activated during chronic disease states, such as cancer.[5]
The antitumorigenic mechanisms of action of Zyflamend are unknown, but according to one study, Zyflamend may suppress activation of nuclear factor-kappa B (NF-kappa B) (a nuclear transcription factor involved in tumorigenesis) and NF-kappa B–regulated gene products.[6]
Preclinical/animal studies
In vitro studies
In a study reported in 2012, human prostate cancer cells were treated in vitro with Zyflamend. Cells treated with the supplement at concentrations ranging from 0.06 to 0.5 μL/mL exhibited dose-dependent decreases in androgen receptor and PSA expression levels compared with cells treated with the dimethyl sulfoxide vehicle control. Prostate cancer cells that were treated with a combination of Zyflamend (0.06 μL/mL) and bicalutamide (25 μM), an androgen receptor inhibitor, showed reductions in cell growth, PSA expression, and antiapoptotic protein expression compared with cells treated with Zyflamend or bicalutamide alone.[7]
Although the individual components of Zyflamend have been shown to influence COX activity, one study examined the effects of the drug on COX-1 and COX-2 expression in prostate cancer cells. The results revealed that Zyflamend, at a concentration of 0.9 μL/mL, inhibited expression of both COX-1 and COX-2. At a concentration of 0.45 μL/mL, the degree of COX-2 inhibition was observed, but the level of COX-1 inhibition was reduced by 50%. At a concentration of 0.1 μL/mL, Zyflamend effectively inhibited growth of prostate cancer cells and increased the level of caspase-3, a proapoptotic enzyme. However, a separate experiment indicated that the prostate cancer cells used in the study (LNCaP cells, which are androgen sensitive) did not express high levels of COX-2, suggesting that Zyflamend’s effects on prostate cancer cells may result from a COX-independent mechanism.[5]
The lipoxygenase isozymes 5-LOX and 12-LOX are also proteins associated with inflammation and tumor growth. In a 2007 study, the effects of Zyflamend on 5-LOX and 12-LOX expression were investigated. The findings indicated that 0.25 μL/mL to 2 μL/mL of Zyflamend produced decreases in 5-LOX and 12-LOX expression in PC3 prostate cancer cells (cells that have high metastatic potential). The supplement also inhibited cell proliferation and induced apoptosis. In addition, Zyflamend treatment resulted in a decrease in Rb phosphorylation (Rb proteins control cell-cycle-related genes). These results indicate that Zyflamend may inhibit prostate cancer cell growth through a variety of mechanisms.[8]
In a 2011 study, human prostate cancer cells were treated with Zyflamend (200 µg/mL). After 48 hours of treatment, a statistically significant reduction in cell growth was observed for Zyflamend-treated cells, compared with control cells (P < .005). In another experiment, prostate cancer cells were treated with insulin-like growth factor-1 (IGF-1; 0–100 ng/mL) alone or in combination with Zyflamend (200 µg/mL). Cells treated with IGF-1 alone exhibited statistically significant, dose-dependent increases in cell proliferation, whereas cells treated with both IGF-1 and Zyflamend showed significant decreases in cell proliferation. Zyflamend was also shown to decrease cellular levels of the IGF-1 receptor and the androgen receptor in prostate cancer cells.[9] A 2014 investigation by this team found that Zyflamend inhibits the expression of class I and class II histone deacetylases (HDAC) and upregulated their downstream target p21 suppressor gene.[10] The extracts of the individual components of the 10 botanicals in Zyflamend were also evaluated in an effort to identify which compounds contributed most to the inhibition of HDAC expression. Chinese goldthread and baikal skullcap appeared to be the most likely major contributors to the overall Zyflamend effect on HDAC expression.
Animal studies
Additional evidence that Zyflamend promotes apoptosis in cancer cells was obtained in laboratory and animal studies reported in 2012.[11] Treatment of human colorectal carcinoma cell lines in vitro with Zyflamend was shown to significantly down regulate expression of antiapoptotic proteins, up regulate expression of Bax (a proapoptotic protein), and increase expression of death receptor 5 (DR5), a receptor important in apoptosis. Moreover, when nude mice with pancreatic cancer cell implants were randomly assigned to receive Zyflamend or a control treatment for 4 weeks, tumor cells from the Zyflamend-treated mice showed significant reductions in antiapoptotic proteins and significantly increased expression of DR5, compared with tumor cells from control-treated animals.
In a 2011 study, mice were also implanted with pancreatic cancer cells and then treated with gemcitabine and/or Zyflamend. The combination treatment resulted in a significantly greater decrease in tumor growth than did treatment with gemcitabine or Zyflamend alone. Other findings from this study suggest that Zyflamend exerted its effects by sensitizing the pancreatic tumors to gemcitabine through suppression of multiple targets linked to tumorigenesis.[12]
Human studies
Intervention studies
In one case report, a patient with HGPIN received Zyflamend 3 times daily for 18 months. Zyflamend did not affect this patient's PSA level, but, after 18 months, repeat core biopsies of the prostate did not show PIN or cancer.[13]
In a 2009 phase I study designed to assess safety and toxicity, patients with HGPIN were assigned to take Zyflamend (780 mg) 3 times daily for 18 months, plus combinations of dietary supplements (i.e., probiotic supplement, multivitamin, green and white tea extract, Baikal skullcap, docosahexaenoic acid, holy basil, and turmeric). Zyflamend and the additional dietary supplements were well tolerated by the patients, and no serious adverse events occurred. After 18 months of treatment, 60% of the study subjects had only benign tissue at biopsy; 26.7% had HGPIN in one core; and 13.3% had prostate cancer.[14]
Adverse effects
Zyflamend was well tolerated in the previously described 2009 clinical study. Mild heartburn was reported in 9 of 23 subjects, but it resolved when the study supplements were taken with food. No serious toxicity or adverse events were reported in the study.[14]
References
- 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. [PUBMED Abstract]
- Gontero P, Marra G, Soria F, et al.: A randomized double-blind placebo controlled phase I-II study on clinical and molecular effects of dietary supplements in men with precancerous prostatic lesions. Chemoprevention or "chemopromotion"? Prostate 75 (11): 1177-86, 2015. [PUBMED Abstract]
- Paur I, Lilleby W, Bøhn SK, et al.: Tomato-based randomized controlled trial in prostate cancer patients: Effect on PSA. Clin Nutr 36 (3): 672-679, 2017. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
Other Prostate Health Supplements
Overview
Many widely available dietary supplements are marketed to support prostate health. African cherry (Pygeum africanum) and beta-sitosterol are two related supplements that have been studied as potential prostate cancer treatments. Note: A separate PDQ summary on PC-SPES is also available.
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 and has recently been classified as an invalid/improbable metabolic panacea (IMP) compound.[9] 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).[10] 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.[11]
Research has also suggested that phytosterols may have anticarcinogenic properties, but the exact mechanisms are unknown.[12] Phytosterols may exert antitumor effects by acting on immune and hormonal systems, or by directly targeting cell cycles and inducing apoptosis in tumor cells.[13]
Beta-sitosterol at very high concentrations (i.e., 16 μM or 6.64 mg/mL) has been shown to significantly inhibit growth of PC-3 prostate cancer cells and induce apoptosis.[14,15] Beta-sitosterol is very poorly bioavailable, with an estimated 0.41% of dietary beta-sitosterol absorbed, and circulating blood levels of about 3 μg/mL to 9 μg/mL in individuals consuming diets containing normal to high amounts of plant-based foods (approximately 1,000 times less than the concentration used in the study).[10,16] Associated with these effects are decreasing levels of cell cycle regulators p21 and p27 in the cancer cells and an increased production of reactive oxygen species.
References
- 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.
- 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 Abstract]
- 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 Abstract]
- 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. [PUBMED Abstract]
- 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 Abstract]
- 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 Abstract]
- 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 Abstract]
- Handratta VD, Vasaitis TS, Njar VC, et al.: Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem 48 (8): 2972-84, 2005. [PUBMED Abstract]
- Nelson KM, Dahlin JL, Bisson J, et al.: The Essential Medicinal Chemistry of Curcumin. J Med Chem 60 (5): 1620-1637, 2017. [PUBMED Abstract]
- Duchateau G, Cochrane B, Windebank S, et al.: Absolute oral bioavailability and metabolic turnover of β-sitosterol in healthy subjects. Drug Metab Dispos 40 (10): 2026-30, 2012. [PUBMED Abstract]
- Tsubakio-Yamamoto K, Nishida M, Nakagawa-Toyama Y, et al.: Current therapy for patients with sitosterolemia--effect of ezetimibe on plant sterol metabolism. J Atheroscler Thromb 17 (9): 891-900, 2010. [PUBMED Abstract]
- Awad AB, Fink CS: Phytosterols as anticancer dietary components: evidence and mechanism of action. J Nutr 130 (9): 2127-30, 2000. [PUBMED Abstract]
- Bradford PG, Awad AB: Phytosterols as anticancer compounds. Mol Nutr Food Res 51 (2): 161-70, 2007. [PUBMED Abstract]
- Awad AB, Burr AT, Fink CS: Effect of resveratrol and beta-sitosterol in combination on reactive oxygen species and prostaglandin release by PC-3 cells. Prostaglandins Leukot Essent Fatty Acids 72 (3): 219-26, 2005. [PUBMED Abstract]
- Scholtysek C, Krukiewicz AA, Alonso JL, et al.: Characterizing components of the Saw Palmetto Berry Extract (SPBE) on prostate cancer cell growth and traction. Biochem Biophys Res Commun 379 (3): 795-8, 2009. [PUBMED Abstract]
- Muti P, Awad AB, Schünemann H, et al.: A plant food-based diet modifies the serum beta-sitosterol concentration in hyperandrogenic postmenopausal women. J Nutr 133 (12): 4252-5, 2003. [PUBMED Abstract]
Changes to This Summary (09/24/2019)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added text to state that on the basis of data from 2014 to 2016, it is estimated that 11.6% of U.S. men will be diagnosed with prostate cancer during their lifetimes (cited National Cancer Institute as reference 1).
This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
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:
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- be cited with text, or
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Prostate Cancer, Nutrition, and Dietary Supplements are:
- Donald I. Abrams, MD (UCSF Osher Center for Integrative Medicine)
- Sangeeta Agarawal, MS, RN, CAS (Helpsy, Inc.)
- Jinhui Dou, PhD (Yiling Pharmaceutical, Inc.)
- 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
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Prostate Cancer, Nutrition, and Dietary Supplements. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/prostate-supplements-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389500]
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