I. Prostate cancer: Epidemiology, selenium and cancer risk

Prostate cancer (PCa) is a complex disease, with a multifactorial etiology involving both genetic and environmental factors. Although there is an association between dietary constituents and the likelihood of developing PCa, a direct causal relationship has not yet been proven. Many antioxidants combine with target tissue and protect the body against harmful affects of free oxygen radicals. Ideal chemopreventive agents should be nontoxic, efficacious, readily available and inexpensive. Epidemiological studies have identified a number of micronutrients, including selenium, as effective PCa prevention agents. If chemoprevention can delay the clinical course of PCa by 5-10 years, there would be a substantial decrease in burden of the disease.

There are several criteria for developing a successful chemoprevention strategy. These include a rational mechanism of action, acceptable level of side effects, demonstrable activity in PCa models and humans, availability of biomarkers and surrogate endpoints to monitor drug activity and efficacy (Ansari et al, 2002). Selenium was recognized about 4 decades ago as an important trace element and is one of the most promising agents being evaluated for PCa prevention. Selenium occurs in organic and inorganic forms (Klein, 2004). The organic forms are found predominantly in grains, fish, meat, poultry, eggs and dietary products. Historically, selenium intake was dependent on the soil selenium content within a region, this effect has been somewhat negated by modern food distribution systems. Japan has the lowest incidence of PCa and their average selenium consumption is 130 mg/day (National Academy of Sciences Recommended Dietaty Allowances, 1998)

There are more than 100 reported studies and more than 2 dozen animal models on the use of selenium. Two thirds of these studies have shown a clear chemopreventive / antitumorigenic effect of selenium in several organs including the mammary gland, liver, skin, pancreas, esophagus, colon and prostate (Combs and Gray, 1998; Ip, 1998). Half of these reports demonstrate that there is more than a 50% reduction in tumor growth with selenium supplementation along with a selenium-replete diet (Combs, 2001). Sodium selenite is more effective in preventing chemically induced tumors, although tissue levels of selenium are higher with selenomethionine (Ip and Hayes, 1989). These reports have heightened interest in additional human selenium chemoprevention studies and have intensified the search for mechanism involved in suppressing tumorigenesis. This review will examine the evidence linking selenium to the prevention of PCa in addition to providing a perspective on the putative in vitro and in vivo mechanisms of chemoprevention.

II. Selenium Biology

A. Forms and dosage of supplemental selenium

Selenium is an essential constituent of extracellular and cellular metalloenzymes, glutathione peroxidase, thyroidal and extrathyroidal deiodinase, thioredoxin reductase, and other selenoproteins (Burk, 1986; Lane et al, 1989; Combs, 1999). Selenium is active in a variety of selenoproteins, playing a preventive role in cancer development. The antitumorigenic effect of selenium has always been associated with supranutritional levels of this constituent. In experimental animals, the suggested levels have been > 1mg / kg diet or 0.7 mg / liter drinking water. These doses are 10 times greater than those required to prevent clinical signs of deficiency. Selenoproteins are expressed maximally at dietary levels (0.5 mg/kg in animals). It is unlikely that the anticarcinogenic effects of supranutritional levels of selenium are related to these proteins. Deprivation of selenium has been thought to contribute to carcinogenesis by limiting the expression of one or more selenoproteins that alter the redox system of cells (Combs, 1999).

Selenium occurs naturally as selenomethionine, Se-methyl-selenomethionine, selenocysteine and selenocystine (Combs and Combs, 1984). The majority of animal model have employed the oxidized inorganic salt. Data from these models cannot be confidently extrapolated to the organo-selenium compounds which are metabolized differently. The beneficial effect of selenium is observed when administered in its naturally occurring form as seleno methionine. Higher animals have no efficient mechanism for methionine synthesis and are unable to synthesize selenomethionine (Combs, 1999). Accordingly, only seleno-cysteine and not seleno-methionine is detected in rats supplemented with selenium as selenite.

B. Selenium bioavailability

Dietary selenium intake depends on soil selenium levels and the origin and types of food that are consumed. A major portion of selenium is stored in the liver, and to a lesser extent in the kidney and muscle. Small amounts exist in plasma and other organs (Drasch et al, 2000; Patrick, 2004). Selenium is highly absorbable with no homeostatic control mechanism for its absorption. Absorption from food is efficient and the average dietary intake is between 20-300 mg/day. Selenium deficiency is correlated with reduced serum selenium concentrations of 85-90 mg/L (Levander and Morris, 1984; Yang et al, 1984; Patrick, 2004).

C. Metabolism of selenium

The metabolism of selenium is dynamic (Ganther, 1999, 2001). A wide array of metabolic products is generated. Selenoprotein can be produced in the body from various selenium sources. Selenomethionine competes with methionine for absorption in the gut and is integrated and stored in body proteins that contain methionine (Ganther, 1971; Hsieh and Ganther, 1975; Bjornstedt et al, 1992; Veres et al, 1994). It may also get converted to selenocysteine and degraded to hydrogen selenide. Selenite is also metabolized to hydrogen selenide complexed with glutathione. Hydrogen selenide is a key metabolite that acts as a precursor for selenoprotein synthesis and is the excreted form of selenium (Behne and Kyriakopoulos, 2001). Hydrogen selenide is methylated and later excreted in the urine and breath resulting in the characteristic “halitosis” or “garlic breath” (the odor of dimethylselenide excreted through the lungs) associated with selenium toxicity (Behne and Kyriakopoulos, 2001). Methylation of selenium produces less toxic selenium compounds. The monomethylated forms of selenium metabolites have powerful effects on carcinogenesis, while lacking some of the toxic effects produced by other forms such as the inorganic selenite (Ganther, 1971; Ip, 1998). Se-methylselenocysteine, a stable methylated selenium compounds thus serves as a reservoir that provides a steady stream of monomethylated selenium so that a critical level is maintained and growth of cells are inhibited (Ganther, 1999).

D. Selenium toxicity

The limit for selenium based on projected lifetime exposure is 5mg/kg body weight/day (US Environmental Protection Agency). The low adverse effect level LOAEL, in humans, has been calculated at 1540±653 mg/day. The no adverse effect level NOAEL, has been calculated at 819±126 mg/day (Whanger et al, 1996). There are reports suggesting that selenium toxicity seen in China requires a daily intake of 2 mg/day (Drasch et al, 2000). There has been no evidence of selenium toxicity observed in the Nutritional Prevention of Cancer Trial at doses of 400 mg of selenium daily. There was no change in hair, nail or skin or garlic breath associated with selenosis. One other selenium trial wherein prostate cancer patients (ascertained by biopsy) were randomized to 1,600 or 3,200 mg/day of selenized yeast for 12 months did not report any selenium-related toxicity, although some side effects were observed (Whanger et al, 1996; Reid et al, 2004; Marshall, 2001).

III. Selenium and prostate cancer

A. Models in defining efficacy of chemoprevention agents

Animal models are central in testing the efficacy of chemopreventive agents. The most feasible, realistic, and potentially effective target for PCa chemoprevention is the progression from PIN to overt cancer. To date more than 100 publications have demonstrated the chemopreventive potential of selenium. These encompass murine studies including spontaneous and induced tumors. Lady transgenics (12T-10) are particularly attractive in this setting, as these animals develop progressive PCa from low-grade intraepithelial neoplasia similar to of PCa, that mimics the variable phenotype of human PCa.

The in vivo effects of selenium have been studied in patients with PCa and BPH. Mean plasma selenium levels have been shown to be lower in PCa patients relative to controls and men with BPH. These findings may reflect chronically lower selenium levels in PCa patients or possibly that disease status caused depletion of serum levels (Criqui et al, 1991; Hardell et al, 1995). In placebo-controlled trials with low soil selenium content, the incidence of PCa was significantly lower in the group that received selenium supplementation (Clark et al, 1996, 1998; Fleet, 1997). In addition, Yoshizawa et al, (1998) found that increased selenium levels from individuals who later developed PCa, were associated with a reduced risk of advanced disease.

In an established orthotopic prostate tumor model, male nude mice were fed a selenium replete diet supplemented with different forms of selenium (sodium selenate, selenomethionine, methylselenocysteine and selenized yeast) at different concentrations. Results revealed that inorganic selenium (sodium selenate significantly retarded the growth of primary prostatic tumors (Corcoran et al, 2004).

B. Mechanism of anti-carcinogenic action of selenium

The inhibitory effects of selenium documented prior to 1985 were in animals that received supplemental dietary selenium. Studies on the inhibitory effect of selenium in vitro were first carried out in the human PCa cell line DU145. Data revealed that concentrations of between 10^-12 M and 10^-8M may have a slight stimulatory effect on growth of DU145 cells but effect gradually declines to 90% of control at 10^-7M. Beyond this there is a marked inhibition, reaching an ID50 between 1x10^-6M and 2x10^-6M, 4% at 10^-5M, and complete cell death occurs at 10^-3M (Webber et al, 1985).

1. Antioxidant protection - oxidative stress

Mutagenic oxidative stress is thought to be a major factor in carcinogenesis, as DNA bases are susceptible to electrophilic attack by reactive oxygen species (ROS), and if not corrected resulted in the expression of a malignant phenotype (Combs, 1999). The hypothesis is that antioxidants scavenge free radicals and thus act as anti-carcinogens. Anticancer effects of sodium selenite, are mediated via a redox mechanism involving induction of oxidative stress. Alterations in intracellular redox state with modification of cellular antioxidants and antioxidant enzymes may inhibit the therapeutic effectiveness of selenium in PCa therapy (Zhong and Oberley, 2001). Selenite was shown to alter intracellular redox status towards an oxidative state by decreasing the ratio of GSH-GSSG. Altering the redox environment of prostate cancer cells with selenite was associated with increased apoptotic potential, sensitizing cells to radiation-induced killing (Husbeck et al, 2005). In a similar study higher manganese superoxide dismutase was seen to play an important role in eliminating superoxide radicals produced as a result of selenite metabolism and contribute to tumor-selective killing by selenite in prostate cancer (Husbeck et al, 2006).

2. Altered carcinogen metabolism

Studies on carcinogen metabolism have indicated that supranutritional selenium supplementation can affect carcinogen metabolism, by reducing the initiation of carcinogenesis. Another group has found that dietary levels of selenium (2mg/kg as selenite) reduced the formation of DNA adducts (Chen et al, 1982).

3. Enhanced immune monitoring

Certain immune functions can be affected by nutritional intake of selenium. Selenium deprivation impairs the development of both B- and T-cell dependent immune responses in animals (Marsh et al, 1986). Certain cytotoxic activities of natural killer cells and polymorphonuclear cells can be impaired by selenium deprivation. Supranutritional selenium intake can enhance immune surveillance of cancerous cells. Selenium has the capability of stimulating cytotoxic activities of NK cells, lymphocytes and lymphokine-activated killer cells (Ip and White, 1987; Lane et al, 1989; Ryan-Harshman and Aldoori, 2005).

4. Molecular basis

i. Cell growth

Epidemiological and clinical data suggest that selenium may prevent PCa, but the biological effect of selenium on normal or malignant prostate cells are not known. Recently, it has been shown that selenium induces retardation of DNA synthesis in primary prostate cells (Morris et al, 2005). Both sodium selenite and selenomethionine (0-500 mM) inhibited the growth of prostate cancer cells (LNCaP, PC3, DU145) in a dose dependent manner compared to prostate stromal, epithelial or smooth muscle cells (Menter et al, 2000). The strongest effects were observed on the androgen dependent LNCaP cells; these were more sensitive to growth suppression with selenite than with selenomethionine.

Selenium in the form of MSA has been shown to significantly down-regulate the expression of prostate-specific antigen transcript and protein in prostate cancer cells. Selenium suppressed the binding of AR to the androgen responsive element site. It has been implicated that that selenium intervention aimed at complementing the amplitude of androgen signaling could be used in controlling the morbidity of the disease (Dong et al, 2004). In a related study methylseleninic acid specifically and rapidly inhibited PSA expression through two mechanisms: inducing PSA protein degradation and suppressing androgen-stimulated PSA transcription. Both these studies implicate important mechanistic implications for prostate specific cancer chemoprevention of selenium (Cho et al, 2004)

ii. Cell cycle

Different chemical forms of selenium have varying effects on the cell cycle (Sinha et al, 1996; Sinha and Medina, 1997; Redman et al, 1998; Menter et al, 2000; Dong et al, 2003). The effects are also cell type dependent. Selenomethionine treated normal prostate cells did not exhibit the same proportion of sub-G0-G1 subpopulations as did the prostate carcinoma cells. Androgen dependent LNCaP cells exhibited a higher sub-G0-G1 cell fraction than PC3 or DU145. We have demonstrated that selenomethionine induced cell cycle arrest with accumulation in S-phase in the androgen dependent LNCaP cells but had no effect on androgen independent PC3 cells. Transfection of a functional androgen receptor into PC-3 cells restored selenium sensitivity, demonstrating that the effect was partly receptor mediated (Venkateswaran et al, 2002).

Selenite treatment has been demonstrated to result in high levels of superoxide production and a sequential increase in levels of total and phosphorylated p53, and p21 (Zhao et al, 2006). These results are suggestive of the fact that the action of selenite is through the production of superoxide to activate p53, thereby inducing mitochondrial translocation of p53.

iii. Cell death/Apoptosis

Methylseleninic acid (MSA) induced apoptosis is accompanied by activation of multiple caspases, mitochondrial release of cytochrome C, PARP cleavage and DNA fragmentation (Jiang et al, 2001, 2002; Hu et al, 2005). These effects are seen only in detached cells, indicating that MSA-induced cell detachment is a prerequisite for caspase activation and the execution of apoptosis. Selenite induced apoptosis is associated with the phosphorylation of c-jun and p38 (Jiang et al, 2001, 2002). Selenite treatment has been shown to cause significant increase in p53 phosphorylation and was an important step that occurred several hours before caspase activation and PARP cleavage (Jiang et al, 2004). Yamaguchi et al, (2005) have recently demonstrated that selenium-based dietary compounds may help to overcome resistance to TRAIL-mediated apoptosis in PCa cells by activating both the extrinsic and intrinsic pathways. Treatment of prostate cancer cells with MSA have provided strong evidence to support an important role of endoplasmic reticulum (ER) stress response in mediating the anticancer effect of selenium (Wu et al, 2005). MSA has been shown to decrease Akt phosphorylation at Thr308 and Ser473, suggesting that selenium-mediated dephosphorylation of Akt was likely to be an additional mechanism in regulating the status of phospho-Akt (Wu et al, 2006).

iv. Gene expression

Studies of the genetic events associated with selenium-induced growth arrest in human prostate cancer have been carried out by gene array (Schlicht et al, 2004; El Bayoumy and Sinha, 2005; Zhao et al, 2004). Methyl-seleninic acid induced cells were subjected to gene profiling. One of the studies revealed a set of genes (2500 out of 12000) that may have been targets of MSA in impeding cell cycle progression (Nelson et al, 1996; Dong et al, 2002, 2003; Zhao et al, 2004). Each of these has been related to signaling pathways that might mediate the outcome of cell cycle blockade by selenium. One other study showed that MSA modulated expression of many androgen-regulated genes in human prostate cancer cells in vitro (Zhao et al, 2004; Dong et al, 2005). A small set of well-characterized androgen-regulated genes, including those with androgen response regulatory elements show expression changes that are reciprocal to those induced by androgens. However, these have not been implicated as direct targets of androgen signaling pathways. It has been clearly shown that selenium affects a multitude of targets, resulting in amplification of the response. The diversity of this response also makes it difficult for transformed cells to escape the inhibitory effect of selenium (Nelson et al, 1996; Dong et al, 2002, 2003).

5. Nuclear Factor kappa Beta (NFkB)

The transcription factor NFkB is a key antiapoptotic factor in mammalian cells (Duffey et al, 1999; Wang et al, 1999; Huang et al, 2001; Gasparian et al, 2002a, b). This has been shown to be suppressed by selenium. NFkB complex is a homo-or heterodimer composed of proteins from the NFkB/Rel family. In non-stimulated cells NFkB resides in the cytoplasm in a complex with the inhibitor protein, together they are named IkB. Selenium inhibition of NFkB activation during early stages of tumorigenesis is a possible mechanism of PCa prevention (Berges et al, 1995). NFkB has been shown to play a role in protecting the cells against diverse apoptotic stimuli including chemo-and radiotherapeutic treatments through the activation of antiapoptotic gene program in cells (Barkett and Gilmore, 1999). There is also evidence that NFkB activation induces cyclin D1, a cyclin that is expressed early in the cell cycle and is crucial to the commitment to DNA synthesis.

6. Human selenium binding protein (hsp56)

Human selenium binding protein hsp56, is the human homologue of a rodent protein implicated in chemoresistance. This is highly expressed in the androgen-sensitive LNCaP cells but not in the androgen-insensitive PC3 cells (Yang and Sytkowski, 1998). The expression of this protein is reversibly down-regulated by androgens in vitro. Recently, we have reported that treatment of LNCaP cells with selenomethionine caused G1 arrest with 80% reduction in the S phase, with no effect on PC3. Selenium sensitivity was restored by the presence of a functional androgen receptor. Together, this suggests that selenium modulation of prostate cancer cell growth is mediated by the androgen receptor as well as by hsp56.

C. Synergy with other Antioxidants and chemotherapeutic agents

Little information is available on the potential synergy between selenium and other antioxidants. We have also demonstrated the synergistic effect of vitamin E and selenomethionine in combination with a 95% reduction in the growth of LNCaP cells in vitro (Venkateswaran et al, 2004a). A highly significant decrease in the incidence of PCa was observed in Lady transgenic animals treated with a combination of antioxidants (Venkateswaran et al, 2004b). MSA has been shown to enhance apoptosis induced by chemotherapeutic agents (adriamycin and taxol) in prostate cancer, suggesting its use to enhance the effect of anti-cancer agents (Vadgama et al, 2000; Zu and Ip, 2003; Hu et al, 2005). The National Cancer Institute and Southwest Oncology Group have initiated a large scale controlled, randomized trial with PCa prevention as the primary end point. This trial named the SELECT (Selenium and Vitamin E Cancer Prevention Trial) is a phase III, double-blind, placebo-controlled, 12 year trial designed to assess the effect of selenium and vitamin E, individually and in combination, on the incidence of PCa as determined by routine clinical management (Pak et al, 2002; Klein et al, 2003a, b; Combs, 2004; Meuillet et al, 2004).

IV. Conclusion

Robust epidemiological and laboratory evidence suggests that selenium in various forms suppresses growth of cancer cells. Selenium has multiple roles in anti-carcinogenesis. Redox-regulated anticancer effects are likely one mechanisms of cancer chemoprevention. Hence, the alteration of intracellular redox state by modifying cellular antioxidants and antioxidants enzymes may regulate the therapeutic effectiveness of selenium in PCa. Chemical transformation of selenium is an important biochemical step in cancer prevention. Selenium acts at an early stage in the progression of carcinogenesis. Selenomethionine not synthesized by humans could have beneficial physiological effects, not shared by other selenium compounds. Hence, future studies should focus on identifying such effects. SELECT, the large-scale, population-based randomized controlled trial will directly test the effect of agents like selenium alone and in combination with vitamin E on the incidence of PCa. Androgens play a critical role in prostate carcinogensis. However, a significant proportion of PCa become androgen unresponsive and refractory to hormonal therapy. Combination studies using antiandrogens and selenium could unravel a multitude of aspects relating to the biochemistry and/or possible functions of selenium both as a chemoprevention and chemotherapeutic agent.

References

Ansari MS, Gupta NP and Hemal AK (2002) Chemoprevention of carcinoma prostate: a review. Int Urol Nephrol 34, 207-214.

Barkett M and Gilmore TD (1999) Control of apoptosis by Rel/NF-kB transcription factors. Oncogene 18, 6910-6924.

Behne D and Kyriakopoulos A (2001) Mammalian selenium-containing proteins. Annu Rev Nutr 21, 453-473.

Berges RR, Vukanovic J, Epstein JI, CarMichel M, Cisek L, Johnson DE, Veltri RW, Walsh PC, Isaacs JT (1995) Implication of cell kinetic changes during the progression of human prostatic cancer. Clin Cancer Res 1, 473-480.

Bjornstedt M, Kumar S and Holmgren A (1992) Selenodiglutathione is a highly efficient oxidant of reduced thioredoxin and a substrate for mammalian thioredoxin reductase. J Biol Chem 267, 8030-8034.

Burk RF (1986) Selenium and cancer: meaning of serum selenium levels. Nutr 116, 1584-1586.

Chen J, Goetchius MP, Combs GF, Jr and Campbell TC (1982) Effects of dietary selenium and vitamin E on covalent binding of aflatoxin to chick liver cell macromolecules. J Nutr 112, 350-355.

Cho SD, Jiang C, Malewicz B, Dong Y, Young CYF, Kang K-S, Lee Y-S, Ip Cand Lu J (2004) Methyl selenium metabolites decrease prostate-specific antigen expression by inducing protein degradation and suppressing androgen-stimulated transcription. Mol Cancer Ther 3, 605-611.

Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, Chow J, Davis LS, Glover RA, Graham GF, Gross EG, Krongrad A, Lesher JL Jr, Park HK, Sanders BB Jr, Smith CL, Taylor JR (1996) A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276, 1957-1963.

Clark LC, Dalkin B, Krongrad A, Combs GF Jr, Turnbull BW, Slate EH, Witherington R, Herlong JH, Janosko E, Carpenter D, Borosso C, Falk S, Rounder J (1998) Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol 81, 730-734.

Combs GF Jr (1999) Chemopreventive mechanisms of selenium. Klin 94 Suppl 3, 18-24.

Combs GF Jr (2001) Impact of selenium and cancer-prevention findings on the nutrition-health paradigm. Cancer 40, 6-11.

Combs GF Jr (2004) Status of selenium in prostate cancer prevention. Br J Cancer 91, 195-199.

Combs GF Jr and Combs SB (1984) The nutritional biochemistry of selenium. Annu Rev Nutr 4, 257-280.

Combs GF Jr and Gray WP (1998) Chemopreventive agents: selenium. Pharmacol Ther 79, 179-192.

Corcoran NM, Najdovska M and Costello AJ (2004) Inorganic selenium retards progression of experimental hormone refractory prostate cancer. J Urol 171, 907-910.

Criqui MH, Bangdiwala S, Goodman DS, Blaner WS, Morris JS, Kritchevsky S, Lippel K, Mebane I, Tyroler HA (1991) Associations with cancer mortality in a population-based prospective case-control study. Ann Epidemiol 1, 385-393.

Dong Y, Ganther HE, Stewart C and Ip C (2002) Identification of molecular targets associated with selenium-induced growth inhibition in human breast cells using cDNA microarrays. Cancer Res 62, 708-714.

Dong Y, Zhang H, Hawthorn L, Ganther HE and Ip C (2003) Delineation of the molecular basis for selenium-induced growth arrest in human prostate cancer cells by oligonucleotide array. J Cancer Res 63, 52-59.

Dong Y, Lee SO, Zhang H, Marshall JR, Gao, AC and Ip C (2004) Prostate specific antigen expression is down-regulated by selenium through disruption of androgen receptor signaling. Cancer Res 64, 19-22.

Dong Y, Zhang H, Gao AC, Marshall JR and Ip C (2005) Androgen receptor signaling intensity is a key factor in determining the sensitivity of prostate cancer cells to selenium inhibition of growth and cancer-specific biomarkers. Mol Cancer Ther 4, 1047-1055.

Drasch G, Mail DS, Schlosser C and Roider G (2000) Content of non-mercury-associated selenium in human tissues. Biol Trace Elem Res 77, 219-230.

Duffey DC, Chen Z, Dong G, Ondrey FG, Wolf JS, Brown K, Siebenlist U, Van Waes C (1999) Expression of a dominant-negative mutant inhibitor-kBa of nuclear factor-kB in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo. Cancer Res 59, 3468-3474.

El Bayoumy K and Sinha R (2005) Molecular chemoprevention by selenium: A genomic approach. Mutat Res 591, 224-236.

Fleet JC (1997) Dietary selenium repletion may reduce cancer incidence in people at high risk who live in areas with low soil selenium. Rev 55, 277-279.

Ganther HE (1971) Reduction of the selenotrisulfide derivative of glutathione to a persulfide analog by glutathione reductase. Biochemistry 10, 4089-4098.

Ganther HE (1999) Selenium metabolism selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase. Carcinogenesis 20, 1657-1666.

Ganther HE (2001) Selenium metabolism and mechanisms of cancer prevention. Med Exp Med Biol 492, 119-130.

Gasparian AV, Yao YJ, Kowalczyk D, Lyakh LA, Karseladze A, Slaga TJ, Budunova IV (2002a) The role of IKK in constitutive activation of NF-kB transcription factor in prostate carcinoma cells. J Cell Sci 115, 141-151.

Gasparian AV, Yao YJ, Lu J, Yemelyanov AY, Lyakh LA, Slaga TJ, Budunova IV (2002b) Selenium compounds inhibit I k B kinase (IKK) and nuclear factor-kB (NF-kB) in prostate cancer cells. Mol Cancer Ther 1, 1079-1087.

Hardell L, Degerman A, Tomic R, Marklund SL and Bergfors M (1995) Levels of selenium in plasma and glutathione peroxidase in erythrocytes in patients with prostate cancer or benign hyperplasia. Eur J Cancer Prev 4, 91-95.

Hsieh HS and Ganther HE (1975) Acid-volatile selenium formation catalyzed by glutathione reductase. Biochemistry 14, 1632-1636.

Hu H, Jiang C, Ip C, Rustum YM and Lu J (2005) Methylseleninic acid potentiates apoptosis induced by chemotherapeutic drugs in androgen-independent prostate cancer cells. Clin Cancer Res 11, 2379-2388.

Hu H, Jiang C, Li G and Lu J (2005) PKB/AKT and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells. Carcinogenesis 26, 1374-1381.

Huang S, Pettaway CA, Uehara H, Bucana CD and Fidler IJ (2001) Blockade of NF-kB activity in human prostate cancer cells is associated with suppression of angiogenesis invasion and metastasis. Oncogene 20, 4188-4197.

Husbeck B, Nonn L, Peehl DM and Knox SJ (2006) Tumor-selective killing by selenite in patient-matched pairs of normal and malignant prostate cells. The Prostate 66, 218-225.

Husbeck B, Peehl DM and Knox SJ (2005) Redox modulation of human prostate carcinoma cells by selenite increases radiation-induced cell killing. Free Radic Biol Med 38, 50-57.

Ip C (1998) Lessons from basic research in selenium and cancer prevention. Nutr 128, 1845-1854.

Ip C and Hayes C (1989) Tissue selenium levels in selenium-supplemented rats and their relevance in mammary cancer protection. Carcinogenesis 10, 921-925.

Ip C and White G (1987) Mammary cancer chemoprevention by inorganic and organic selenium: single agent treatment or in combination with vitamin E and their effects on in vitro immune functions. Carcinogenesis 8, 1763-1766.

Jiang C, Hu H, Malewicz B, Wang Z and Lu J (2004) Selenite-induced p53 ser-15 phosphorylation and caspase-mediated apoptosis in LNCaP human prostate cancer cells. Mol Cancer Ther 3, 877-884.

Jiang C, Wang Z, Ganther H and Lu J (2001) Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells. Cancer Res 61, 3062-3070.

Jiang C, Wang Z, Ganther H and Lu J (2002) Distinct effects of methylseleninic acid versus selenite on apoptosis cell cycle and protein kinase pathways in DU145 human prostate cancer cells. Mol Cancer Ther 1, 1059-1066.

Klein EA (2004) Selenium: epidemiology and basic science. Urol 171, 50-53.

Klein EA, Lippman SM, Thompson IM, Goodman PJ, Albanes D, Taylor PR, Coltman C (2003a) The selenium and vitamin E cancer prevention trial. World J Urol 21, 21-27.

Klein EA, Thompson IM, Lippman SM, Goodman PJ, Albanes D, Taylor PR, Coltman C (2003b) SELECT: the selenium and vitamin E cancer prevention trial. Urol Oncol 21, 59-65.

Lane HW, Medina D and Wolfe LG (1989) Proposed mechanisms for selenium-inhibition of mammary tumorigenesis (review). J In Vivo 3, 151-160.

Levander OA and Morris VC (1984) Dietary selenium levels needed to maintain balance in North American adults consuming self-selected diets. Nutr Am J Clin Nutr 39, 809-815.

Marsh JA, Combs GF, Jr, Whitacre ME and Dietert RR (1986) Effect of selenium and vitamin E dietary deficiencies on chick lymphoid organ development. Proc Soc Exp Biol Med 182, 425-436.

Marshall JR (2001). Larry Clark's legacy: randomized controlled, selenium-based prostate cancer chemoprevention trials. Nutr Cancer 40, 74-77.

Menter DG, Sabichi AL and Lippman SM (2000) Selenium effects on prostate cell growth. Nutr Cancer Epidemiol Biomarkers Prev 9, 1171-1182.

Meuillet E, Stratton S, Prasad Cherukuri D, Goulet AC, Kagey J, Porterfield B, Nelson MA (2004) Chemoprevention of prostate cancer with selenium: an update on current clinical trials and preclinical findings. J Cell Biochem 91, 443-458.

Morris JD, Pramanik R, Zhang X, Carey AM, Ragavan N, Martin FL, Muir GH (2005) Selenium- or quercetin-induced retardation of DNA synthesis in primary prostate cells occurs in the presence of a concomitant reduction in androgen-receptor activity. Br Cancer Lett , ahead of printing.

National Academy of Sciences Recommended Dietaty Allowances (1998) 10th ed.Washington DC: National Academy Press., 217-224.

Nelson KK, Bacon B and Christensen MJ (1996) Selenite supplementation decreases expression of MAZ in HT29 human colon adenocarcinoma cells. Nutr Cancer 26, 73-81.

Pak RW, Lanteri VJ, Scheuch JR and Sawczuk IS (2002) Review of vitamin E and selenium in the prevention of prostate cancer: implications of the selenium and vitamin E chemoprevention trial. Integr Cancer Ther 1, 338-344.

Patrick L (2004) Selenium biochemistry and cancer: a review of the literature. J Med Rev 9, 239-258.

Redman C, Scott JA, Baines AT, Basye JL, Clark LC, Calley C, Roe D, Payne CM, Nelson MA (1998) Inhibitory effect of selenomethionine on the growth of three selected human tumor cell lines. Cancer Lett 125, 103-110.

Reid ME. Stratton MS. Lillico AJ. Fakih M. Natarajan R. Clark LC. Marshall JR (2004) A report of high-dose selenium supplementation: response and toxicities. J Trace Elem Med Biol 18, 69-74.

Ryan-Harshman M and Aldoori W (2005) The relevance of selenium to immunity cancer and infectious/inflammatory diseases. Can J Diet Pract Res 66, 98-102.

Schlicht M, Matysiak B, Brodzeller T, Wen X, Liu H, Zhou G, Dhir R, Hessner MJ, Tonellato P, Suckow M, Pollard M, Datta MW (2004) Cross-species global and subset gene expression profiling identifies genes involved in prostate cancer response to selenium. BMC Genomics 5, 58.

Sinha R and Medina D (1997) Inhibition of cdk2 kinase activity by methylselenocysteine in synchronized mouse mammary epithelial tumor cells. Carcinogenesis 18, 1541-1547.

Sinha R, Said TK and Medina D (1996) Organic and inorganic selenium compounds inhibit mouse mammary cell growth in vitro by different cellular pathways. Cancer Lett 107, 277-284.

Vadgama JV, Wu Y, Shen D, Hsia S and Block J (2000) Effect of selenium in combination with Adriamycin or Taxol on several different cancer cells. Anticancer Res 20, 1391-1414.

Venkateswaran V, Fleshner NE and Klotz LH (2004a) Synergistic effect of vitamin E and selenium in human prostate cancer cell lines. Prostate Cancer Prostatic Dis 7, 54-56.

Venkateswaran V, Fleshner NE, Sugar LM and Klotz LH (2004b) Antioxidants block prostate cancer in lady transgenic mice. Cancer Res 64, 5891-5896.

Venkateswaran V, Klotz LH and Fleshner NE (2002) Selenium modulation of cell proliferation and cell cycle biomarkers in human prostate carcinoma cell lines. Cancer Res 62, 2540-2545.

Veres Z, Kim IY, Scholz TD and Stadtman TC (1994) Selenophosphate synthetase. Enzyme properties and catalytic reaction. Altern J Biol Chem 269, 10597-10603.

Wang CY, Cusack JC Jr, Liu R and Baldwin AS, Jr (1999) Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kB. Nat Med 5, 412-417.

Webber MM, Perez-Ripoli EA and James GT (1985) Inhibitory effect of selenium on the growth of DU-145 human prostate carcinoma cells in vitro. Biochem Biophys Res Commun 130, 603-609.

Whanger P, Vendeland S, Park YC and Xia Y (1996) Metabolism of subtoxic levels of selenium in animals and humans. Adv Ann Clin Lab Sci 26, 99-113.

Wu Y, Warren MA, Wallace PK and Ip C (2006) Delineating the mechanism by which selenium deactivates Akt in prostate cancer cells. Mol Cancer Ther 5, 246-252.

Wu Y, Zhang H, Dong Y, Park Y-M and Ip C (2005) Endoplasmic reticulum stress signal mediators are targets of selenium action. Cancer Res 65, 9073-9079.

Yamaguchi K, Uzzo RG, Pimkina J, Makhov P, Golovine K, Crispen P, Kolenko VM (2005) Methylseleninic acid sensitizes prostate cancer cells to TRAIL-mediated apoptosis. Oncogene 24, 5868-5877.

Yang GQ, Chen JS, Wen ZM, Ge KY, Zhu LZ, Chen XC, Chen XS (1984) The role of selenium in Keshan disease. Adv Nutr Res 6, 203-231.

Yang M and Sytkowski AJ (1998) Differential expression and androgen regulation of the human selenium-binding protein gene hSP56 in prostate cancer cells. Cancer Res 58, 3150-3153.

Yoshizawa K, Willett WC, Morris SJ, Stampfer MJ, Spiegelman D, Rimm EB, Giovannucci E (1998) Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. Natl Cancer Inst 90, 1219-1224.

Zhao H, Whitfield ML, Xu T, Botstein D and Brooks JD (2004) Diverse effects of methylseleninic acid on transcriptional program of human prostate cancer cells. Mol Biol 15, 506-519.

Zhao R, Xiang N, Domann FE, Zhong W (2006) Expression of p53 enhances selenite-induced superoxide production and apoptosis in human prostate cancer cells, Cancer Res 66, 2296-2304.

Zhong W and Oberley TD (2001) Redox-mediated effects of selenium on apoptosis and cell cycle in the LNCaP human prostate cancer cell line. Cancer Res 61, 7071-7078.

Zu K and Ip C (2003) Synergy between selenium and vitamin E in apoptosis induction is associated with activation of distinctive initiator caspases in human prostate cancer cells. Cancer Res 63, 6988-6995.

Vasundara Venkateswaran

Review Article

Received: 18 January 2006; Accepted: 7 March 2006; electronically published: March 2006

References