Selenium is an essential element that is specifically incorporated as selenocystein into selenoproteins. It is a potent modulator of eukaryotic cell growth with strictly concentration-dependant effects. Lower concentrations are necessary for cell survival and growth, whereas higher concentrations inhibit growth and induce cell death. It is well established that selenium has cancer preventive effects, and several studies also have shown that it has strong anticancer effects with a selective cytotoxicity on malignant drug-resistant cells while only exerting marginal effects on normal and benign cells. This cancer-specific cytotoxicity is likely explained by high affinity selenium uptake dependent on proteins connected to multidrug resistance. One of the most studied selenoproteins in cancer is thioredoxin reductase (TrxR) that has important functions in neoplastic growth and is an important component of the resistant phenotype. Several reports have shown that TrxR is induced in tumor cells and pre-neoplastic cells, and several commonly used drugs interact with the protein. In this review, we summarize the current knowledge of selenium as a potent preventive and tumor selective anticancer drug, and we also discuss the potential of using the expression and modulation of the selenoprotein TrxR in the diagnostics and treatment of cancer.

The selenium salt selenite (SeO3 2؊ ) is cytotoxic in low to moderate concentrations, with a remarkable specificity for cancer cells resistant to conventional chemotherapy. Our data show that selenium uptake and accumulation, rather than intracellular events, are crucial to the specific selenite cytotoxicity observed in resistant cancer cells. We show that selenium uptake depends on extracellular reduction, and that the extracellular environment is a key factor specific to selenite cytotoxicity. The extracellular reduction is mediated by cysteine, and the efficacy is determined by the uptake of cystine by the x c ؊ antiporter and secretion of cysteine by multidrug resistance proteins, both of which are frequently overexpressed by resistant cancer cells. This mechanism provides molecular evidence for the existence of an inverse relationship between resistance to conventional chemotherapy and sensitivity to selenite cytotoxicity, and highlights the great therapeutic potential in treating multidrug-resistant cancer.2Ϫ ) efficiently inhibits the growth of malignant cells and studies suggest an inverse relationship between resistance to cytotoxic drugs and sensitivity to selenite (SeO 3 2Ϫ ) (1, 2). A major mechanism of selenite cytotoxicity is thought to be the generation of oxidative stress through intracellular redox cycling of the selenium metabolite selenide with oxygen and cellular thiols, producing nonstoichiometric amounts of superoxide and cellular disulfides. The induction of oxidative stress and consequent apoptosis has been demonstrated in numerous cancer cell lines (2-8), but why this occurs only in malignant cells at easily achievable selenium plasma concentrations remains unclear.With the assumption that the mechanistic explanation is intracellular, studies on differences in cellular uptake have been neglected. Already in the 1960s, selenite (SeO 3 2Ϫ ) was being used experimentally as a tumor-localizing agent. Neoplasms could be detected in brain and thorax in human subjects through i.v. administration of radioactive selenite ( 75 Se) (9). Although at that time the cancer-specific cytotoxic effects of selenite were unknown, and low doses were used (approximately in the nM range in blood) (9), early findings clearly demonstrated that cancer cells enrich selenium in vivo. These findings, combined with current knowledge of selenite's toxic effects on malignant cells, raise the possibility of a cancer-specific high-affinity selenium uptake mechanism that might explain cancer-specific selenite cytotoxicity at therapeutic selenite concentrations (M range).In yeast, millimolar tolerance to selenite can be reduced to the micromolar range by the presence of excessive thiols in the growth medium through high-affinity uptake of a more reduced form of selenite, possibly selenide (10). High-affinity uptake of selenium through the addition of extracellular thiols also has been demonstrated in a keratinocyte model (11) using nanomolar concentrations of selenite. Selenium uptake was prevented in keratinocytes by the ...

The Grx (glutaredoxin) proteins are oxidoreductases with a central function in maintaining the redox balance within the cell. In the present study, we have explored the reactions between selenium compounds and the glutaredoxin system. Selenite, GS-Se-SG (selenodiglutathione) and selenocystine were all shown to be substrates of human Grx1, implying a novel role for the glutaredoxins in selenium metabolism. During the past few years, selenium has further evolved as a potential therapeutic agent in cancer treatment, and a leading mechanism of cytotoxicity is the generation of ROS (reactive oxygen species). Both selenite and GS-Se-SG were reduced by Grx1 and Grx2 in a non-stoichiometric manner due to redox cycling with oxygen, which in turn generated ROS. The role of Grx in selenium toxicity was therefore explored. Cells were treated with the selenium compounds in combination with transient overexpression of, or small interfering RNA against, Grx1. The results demonstrated an increased viability of the cells during silencing of Grx1, indicating that Grx1 is contributing to selenium toxicity. This is in contrast with TrxR (thioredoxin reductase), which previously was shown to protect cells from selenium cytotoxicity, verifying a diverse role between Grx and TrxR in selenium-mediated cytotoxicity. Furthermore, selenium treatment led to a marked increase in protein glutathionylation and cysteinylation that potentially can influence the activity and function of several proteins within the cell.