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.
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. A number of selenoproteins have been identified in humans, including selenoprotein P (SEPP), which is the main selenium carrier in the body and is important for selenium homeostasis.
Food sources of selenium include meat, vegetables, and nuts. The selenium content of the soil where food is raised determines the amount of selenium found in plants and animals. For adults, the recommended daily allowance for selenium is 55 µg /d. Most dietary selenium occurs as selenocysteine or selenomethionine. Selenium accumulates in the thyroid gland, liver, pancreas, pituitary gland, and renal medulla.
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. Some clinical trials have suggested that high levels of selenium may be associated with diabetes  and high cholesterol.
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. 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.
There is evidence that selenoproteins may be associated with carcinogenesis. For example, reduced expression of glutathione peroxidase 3 and selenoprotein P have been observed in some tumors, while increased expression of glutathione peroxidase 2 occurs in colorectal and lung tumors.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. In a 2011 study, prostate cancer cells were treated with various forms of selenium; selenite and methylseleninic acid (MeSeA) had the greatest cytotoxic effects.
Studies have suggested that selenium nanoparticles may be less toxic to normal tissues than are other selenium compounds. One study investigated the effects of selenium nanoparticles on prostate cancer cells. The treated cells had decreased activity of the androgen receptor, which led to apoptosis and growth inhibition.Sodium selenite
In a 2010 study, prostate cancer cells treated with sodium selenite (a natural form of selenium) exhibited increased levels of p53 (a tumor suppressor). Findings also revealed that p53 may play a key role in selenium-induced apoptosis.
In another study, cells from the prostate cancer cell line LNCaP were modified to overexpress each of four antioxidant enzymes and 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 how effective selenium is in inhibiting those cells.
One study treated prostate cancer cells and benign prostatic hyperplasia (BPH) cells with sodium selenite. Growth of LNCaP cells was stimulated by noncytotoxic, low concentrations of sodium selenite; while growth inhibition occurred in 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. 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, and prostate tissue concentrations are about 1.5 µg/g.Animal studies
Animal studies of selenium and prostate cancer have predominantly focused on biodistribution models commonly utilized to assess potential prevention strategies. A 2012 study investigated whether various forms of selenium (i.e., SeMet and 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 to a similar degree. The different forms of selenium supplementation showed no significant differences in DNA damage, proliferation, or apoptosis in the prostate.
At least one study has compared these three forms of selenium in athymic nude mice injected with human prostate cancer cells and found that MSeA was more effective in inhibiting tumor growth than was SeMet or selenite. 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 to selenium-containing diets. However, in young mice, tumor development and histopathology were not affected by dietary selenium.
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. Treatment with MSeA and MSeC resulted in slower progression of prostatic intraepithelial neoplasia (PIN) lesions, decreased cell proliferation, and increased apoptosis compared to 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. Another study suggests that MSeA may inhibit cell growth and increase apoptosis by inactivating PKC isoenzymes.Human 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 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. In another prospective pilot study, prostate cancer patients had significantly lower whole blood selenium levels than did healthy males. 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.
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. 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. 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.
A retrospective analysis of prostate cancer patients and healthy controls showed an association between aggressive prostate cancer and decreased selenium and SEPP status. In the Physicians' Health Study, links between SNPs in the selenoprotein P 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. In one study, the direction of the association between blood selenium levels and advanced prostate cancer incidence differed according to which of two polymorphisms of the gene encoding the enzyme manganese superoxide dismutase (SOD2) a patient had. For men with the 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 V allele.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 the end of the study. Compared to 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.
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).
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 LDL and total cholesterol.
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 selenized 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.
In 2013, results of a phase 3 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-selenium 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. 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.The Selenium and Vitamin E Cancer Prevention Trial (SELECT)
On the basis of findings of from earlier studies,[8,36] the Selenium and Vitamin E Cancer Prevention Trial (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. 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 daily) and a placebo, selenium (L-selenomethionine, 200 µg daily) 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.
Initial results of SELECT were published in 2009. There were no statistically significant differences in rates of prostate cancer in the four groups. In the vitamin E–alone group, there was a nonsignificant increase in rates of prostate cancer (P = .06); in the selenium–alone group, there was a nonsignificant increase in incidence of diabetes mellitus (P = .16). On the basis of those findings, the data and safety monitoring committee recommended that participants stop taking the study supplements.
Updated results were published in 2011. When compared with 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.
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 selenized yeast had been used in previous studies. SELECT researchers chose selenomethionine because it was the major component of selenized yeast and because selenite was not absorbed well by the body, resulting in lower selenium stores. In addition, there were concerns over product consistency with high-selenium yeast. However, selenomethionine is involved in general protein synthesis and can have numerous metabolites such as methylselenol, which may have antitumor properties.[42,43]
Baseline selenium levels may have played an important role in the study. SELECT participants had higher serum selenium levels at the start of the study than did subjects in other studies, which may have affected outcomes of selenium supplementation. It has been suggested that selenium may have chemopreventive effects in men who start with low levels of selenium.Current Clinical Trials
Check NCI’s list of cancer clinical trials for CAM clinical trials on selenium that are actively enrolling patients.
General information about clinical trials is also available from the NCI Web site.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.[33,34] However, in SELECT, selenium supplementation was associated with a nonsignificant increase in incidence of diabetes mellitus (P = .08).References
- Brown KM, Arthur JR: Selenium, selenoproteins and human health: a review. Public Health Nutr 4 (2B): 593-9, 2001. [PUBMED Abstract]
- Tanguy S, Grauzam S, de Leiris J, et al.: Impact of dietary selenium intake on cardiac health: experimental approaches and human studies. Mol Nutr Food Res 56 (7): 1106-21, 2012. [PUBMED Abstract]
- Mordan-McCombs S, Brown T, Zinser G, et al.: Dietary calcium does not affect prostate tumor progression in LPB-Tag transgenic mice. J Steroid Biochem Mol Biol 103 (3-5): 747-51, 2007. [PUBMED Abstract]
- Bodnar M, Konieczka P, Namiesnik J: The properties, functions, and use of selenium compounds in living organisms. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 30 (3): 225-52, 2012. [PUBMED Abstract]
- Sunde RA: Selenium. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 711-8.
- Boosalis MG: The role of selenium in chronic disease. Nutr Clin Pract 23 (2): 152-60, 2008 Apr-May. [PUBMED Abstract]
- Davis CD, Tsuji PA, Milner JA: Selenoproteins and cancer prevention. Annu Rev Nutr 32: 73-95, 2012. [PUBMED Abstract]
- Clark LC, Combs GF Jr, Turnbull BW, et al.: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276 (24): 1957-63, 1996. [PUBMED Abstract]
- Pinto JT, Sinha R, Papp K, et al.: Differential effects of naturally occurring and synthetic organoselenium compounds on biomarkers in androgen responsive and androgen independent human prostate carcinoma cells. Int J Cancer 120 (7): 1410-7, 2007. [PUBMED Abstract]
- Lunøe K, Gabel-Jensen C, Stürup S, et al.: Investigation of the selenium metabolism in cancer cell lines. Metallomics 3 (2): 162-8, 2011. [PUBMED Abstract]
- Kong L, Yuan Q, Zhu H, et al.: The suppression of prostate LNCaP cancer cells growth by Selenium nanoparticles through Akt/Mdm2/AR controlled apoptosis. Biomaterials 32 (27): 6515-22, 2011. [PUBMED Abstract]
- 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]
- Xiang N, Zhao R, Zhong W: Sodium selenite induces apoptosis by generation of superoxide via the mitochondrial-dependent pathway in human prostate cancer cells. Cancer Chemother Pharmacol 63 (2): 351-62, 2009. [PUBMED Abstract]
- Kandaş NO, Randolph C, Bosland MC: Differential effects of selenium on benign and malignant prostate epithelial cells: stimulation of LNCaP cell growth by noncytotoxic, low selenite concentrations. Nutr Cancer 61 (2): 251-64, 2009. [PUBMED Abstract]
- Niskar AS, Paschal DC, Kieszak SM, et al.: Serum selenium levels in the US population: Third National Health and Nutrition Examination Survey, 1988-1994. Biol Trace Elem Res 91 (1): 1-10, 2003. [PUBMED Abstract]
- Takata Y, Morris JS, King IB, et al.: Correlation between selenium concentrations and glutathione peroxidase activity in serum and human prostate tissue. Prostate 69 (15): 1635-42, 2009. [PUBMED Abstract]
- 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]
- 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 Jr, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011. [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]
- 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]
- Rayman MP, Combs GF Jr, Waters DJ: Selenium and vitamin E supplementation for cancer prevention. JAMA 301 (18): 1876; author reply 1877, 2009. [PUBMED Abstract]