Cancer chemoprevention: selenium as a prooxidant, not an antioxidant.
Although the average daily dietary selenium (Se) intake in the United States is consistently above the adult RDA of 55 microg Se/day, supranutritional supplements of 200 microg Se/day have been shown to provide chemopreventive benefits against several cancers, particularly prostate cancer. The hypothesis herein contends that selenium compounds with the greatest anticarcinogenic potency are likely to be sodium selenite with Se in the +4 oxidation state and methylseleninic acid. These compounds exert their cancer chemopreventive effects by directly oxidizing critical thiol-containing cellular substrates, and are more effective than the more frequently preferred (used) supplements of selenomethionine and Se-methylselenocysteine that lack oxidation capability. Selenate (+6 Se) the immediate precursor of selenite (+4 Se) can be metabolically reduced, and although less potent than the +4 Se compounds cited above, appears to be a more effective anticarcinogen than organic forms of dietary selenium. Apoptosis, an important, Se-induced anticarcinogenic mechanism, is accomplished by the direct oxidation of vicinal sulfhydryl groups in cysteine clusters within the catalytic domains of cellular enzymes (e.g., protein kinase C), and by the production of CH3Se-, which reacts with O2 to generate superoxide and other reactive oxygen species (ROS). Activated oncogenes "prime" cells for Se-induced prooxidative apoptosis thereby providing the needed margin for "killing" cancer cells while leaving normal, healthy cells unharmed. Selenoethers, such as selenomethionine and Se-methylselenocysteine are not oxidizing agents, and first, must be converted to methylselenol (CH3Se-) that can be directly oxidized to methylseleninic acid. The addition of methioninase, to selenomethionine, or beta-lyase to Se-methylselenocysteine, rapidly produces significant amounts of methylselenol, which may be oxidized to methylseleninic acid or may react with O2 to produce superoxide and ROS, resulting in anticarcinogenic activities comparable to selenite or methylseleninic acid. The relatively large amounts of selenomethionine or Se-methylselenocysteine needed to produce apoptosis in cancer cells compared with selenite or methylseleninic acid are a probable consequence of low tissue levels of the required enzymes. Even though many studies have consistently shown that selenomethionine is an ineffective anticarcinogen at doses corresponding to those currently allowed by the FDA, it has been chosen as the Se intervention agent in the 32,500-man (phase III), NCI-funded SELECT trial, which tests the effectiveness of dietary supplements of dietary supplements of Se and tocopherol, individually or in combination, in the prevention of prostate cancer. In 2013, when the data are in, the value of using Se supplements for cancer chemoprevention is likely to be underestimated.