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The biological activity of selenium is dependent upon its speciation. We aim to integrate selenium speciation and metabolism into a discussion of the mechanisms by which selenium exerts its biological activity. First, we present the current status of selenium in the prevention of cancer, cardiovascular and neurodegenerative diseases with particular attention paid to the results of major chemoprevention trials involving selenium supplementation. A comprehensive review of the current understanding of the metabolism of common dietary selenium compounds - selenite, selenomethionine, methylselenocysteine and selenocystine - is presented, with discussion of the evidence for the various metabolic pathways and their products. The antioxidant, prooxidant and other mechanisms of the dietary selenium compounds have been linked to their disease prevention and treatment properties. The evidence for these various mechanisms -in vitro, in cells and in vivo- is evaluated with emphasis on the selenium metabolites involved. We conclude that dietary selenium compounds should be considered prodrugs, whose biological activity will depend on the activity of the various metabolic pathways in, and the redox status of, cells and tissues. These factors should be considered in future laboratory research and in selecting selenium compounds for trials of disease prevention and treatment by selenium supplementation.

We have shown that, in contrast to selenomethionine (SeMet) or selenite, methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) exert prostate cancer (PCa) inhibitory effect in preclinical models. Here we investigated the prostate proteome signatures of mice treated with each selenium (Se) form for hypothesis generation concerning their potential in vivo molecular targets and cancer risk modification. Nude mice bearing subcutaneous PC-3 xenografts were treated daily with each Se form (3 mg Se/kg) orally for 45 days. Five prostates were pooled from each group. Their proteomes were profiled by LC-MS/MS with iTRAQ labeling. Of the 1,088 proteins identified, 72 were significantly modulated by one or more Se forms. MSeA and MSeC each induced separate sets of tumor suppressor proteins and suppressed different onco-proteins. Proteins induced by selenite and shared with MSeC were related to energy metabolism (e.g., fatty-acid synthase), and those induced by SeMet included vimentin and heat-shock protein-70, favoring cancer growth. While proteome changes induced by MSeA were associated with PCa risk reduction, desirable risk-reducing signatures induced by MSeC were counterbalanced by risk-promoting patterns shared with selenite and SeMet. We propose that the balance of oncogenic vs. suppressor protein patterns in the prostate may impact the direction of PCa risk modification by a given selenium.

Because the Selenium (Se) and Vitamin E Cancer Prevention Trial (SELECT) failed to show the efficacy of selenomethionine for prostate cancer prevention, there is a critical need to identify safe and efficacious Se forms for future trials. We have recently shown significant preventive benefit of methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) in the transgenic adenocarcinoma mouse prostate (TRAMP) model by oral administration. The present work applied iTRAQ proteomic approach to profile protein changes of the TRAMP prostate and to characterize their modulation by MSeA and MSeC to identify their potential molecular targets. Dorsolateral prostates from wild-type mice at 18 weeks of age and TRAMP mice treated with water (control), MSeA, or MSeC (3 mg Se/kg) from 8 to 18 weeks of age were pooled (9-10 mice per group) and subjected to protein extraction, followed by protein denaturation, reduction, and alkylation. After tryptic digestion, the peptides were labeled with iTRAQ reagents, mixed together, and analyzed by two-dimensional liquid chromatography/tandem mass spectrometry. Of 342 proteins identified with >95% confidence, the expression of 75 proteins was significantly different between TRAMP and wild-type mice. MSeA mainly affected proteins related to prostate functional differentiation, androgen receptor signaling, protein (mis)folding, and endoplasmic reticulum-stress responses, whereas MSeC affected proteins involved in phase II detoxification or cytoprotection, and in stromal cells. Although MSeA and MSeC are presumed precursors of methylselenol and were equally effective against the TRAMP model, their distinct affected protein profiles suggest biological differences in their molecular targets outweigh similarities., (2010 AACR.)

Selenium is an important trace element with anti-cancer properties. In the present study, the apoptosis-inducing effects of organic selenium derivatives, namely methyl-L-selenocysteine and selenomethionine, were evaluated in vitro on human tumour-derived cell lines from breast, liver, colon, brain, skin and a non-tumorigenic line of epithelial origin. Apoptosis was assessed by cell-death detection immunoassay on cytoplasmic cell lysates. Breast carcinoma cells were highly sensitive to the organic selenium compounds, manifesting apoptosis at concentrations as low as 0.113 microm (0.0205 microg/ml) selenium. By contrast, non-tumorigenic mammary epithelial cells displayed poor sensitivity to selenium, requiring a substantially high concentration of the trace element of 87.9 microm (16.0 microg/ml). The cell lines derived from hepatoma and neuroblastoma showed intermediate sensitivity, with colon carcinoma cells manifesting the lowest sensitivity to the trace element. These results indicate intrinsic differences in the sensitivity of human tumour derivatives to selenium-mediated apoptosis, providing experimental support for the development of organic selenium compounds as anti-neoplastic agents against solid tumours displaying selective apoptotic sensitivity to these compounds.

Background: Selenium is an essential trace nutrient necessary for the normal function of the immune system. Selenium compounds protect mice against ultraviolet (UV) B-induced tumours, probably by preventing oxidative damage to the host skin cells and to the host immune system. One possible mechanism of protection is that selenium can prevent oxidative stress-induced release of cytokines such as interleukin (IL)-10, which could suppress cell-mediated immunity., Objectives: To determine whether selenium compounds can inhibit UVB induction of IL-10 protein in murine keratinocytes., Methods: The murine keratinocyte cell line PAM 212 was treated with or without selenomethionine (50-200 nmol L-1) or sodium selenite (1-50 nmol L(-1)) for 24 h before exposure to 200 J m(-2) UVB. The cells were stained with an antibody to IL-10, 24 h after irradiation., Results: Preincubation with both selenium compounds inhibited UVB induction of IL-10 immunostaining, although selenomethionine was more effective. Pretreatment with 200 nmol L(-1) selenomethionine decreased IL-10 immunostaining to levels seen in the unirradiated controls., Conclusions: The protective effects of selenium against UVB-induced skin cancer in murine models may result, in part, from its ability to inhibit release of cytokines that are capable of suppressing cell-mediated immunity.