Dietary selenium deficiency is associated with an increased risk of          carcinogenesis and of increased mortality (15,16). Multiple other epidemiologic studies have suggested that higher selenium blood levels are protective against the development of various solid tumors (17-26).

Mechanisms of action against cancer

Selenium-containing nutrients exert their anti-cancer effects not only by protecting cell membranes and DNA via their antioxidant and reactive oxygen species scavenging actions, but by regulating nuclear factor activities including nuclear factor kappa B and p53, among others.           

            Research on the ways in which selenium-containing compounds prevent cancer formation and/or destroy cancer cells has progressed on several fronts. Inhibition of cell invasion, DNA repair, and stimulation of transforming growth factor beta signaling are of recent interest. The effect of selenium-containing compounds on gene expression is of special interest. A large number of selenium-responsive genes with diverse biological functions have now been identified. These genes fall into 12 clusters of distinct kinetics patterns. The expression changes of 10 genes known to be critically involved in cell cycle regulation have been noted so far.

            Selenium compounds also inhibit signaling enzymes such as protein kinase C (PKC) that play crucial roles in tumor promotion. The selenoprotein Sep15 has now been shown to have redox function. The selenium-containing nutrient, selenomethionine has been shown to regulate the tumor suppressor p53 by the redox factor refl-dependent redox mechanism. Studies continue to support evidence that one important pathway is that many selenium-containing nutrients can be converted in the body to methylselenol.

            Methylselenol has been shown to block expansion of pre-malignant cells forming into fully developed cancers. Several pathways have been proposed that could explain how selenium-containing compounds could block mutated cells from progressing to cancer. Methylseleninic acid, formed from the metabolism of selenium-containing nutrients, has been shown to inhibit NF-kappa B and regulate I kappa B in prostate cancer cells. A representative of the hydrogen selenide metabolic pool has been found to protect liver cells against damage to DNA.

            Selenium-containing compounds may exert their anticarcinogenic action via both selenoproteins and smaller non-proteins and metabolites. The mechanisms for these anticarcinogenic actions include the antioxidant effects of selenium mediated through glutathione peroxidase, modification   of carcinogen    metabolism, effects on the immune system and endocrine         functions, production of cytotoxic metabolites, inhibition of protein synthesis and enzymes that catalyze cell proliferation, as well as induction of apoptosis.

            Some of the selenoproteins have antioxidant and radical-savaging roles which may account for their cancer-protective effect. However, reduced levels of several individual selenoproteins may account for increased risk of cancer other than antioxidant effects (9,10)

            In 1978, Schrauzer discussed six mechanisms of action of selenium against cancer. These included the stimulation of immune response, protection against radicals, oxidants and radiation, detoxification of environmental mutagens or carcinogens, liver protection, maintenance of cellular respiration and nonspecific effects. (27)

            The detoxification of environmental carcinogens and the interference with the metabolism of carcinogens is an important consideration that is often overlooked. Selenium may react directly with carcinogens to prevent their binding to DNA. Also reactive selenium metabolites can render carcinogens non-carcinogenic. Ip and Lisk have shown that selenium compounds can raise the levels of xenobiotic enzymes in the liver, such as cytochrome P450 and mixed function oxidases responsible for the detoxification of carcinogens. (28)

            A 2001 review by Spallholz lists five mechanisms for the carcinostatic properties of selenium; selenium’s antioxidant role, its ability to enhance immunity, its effect on the metabolism of carcinogens, its role in protein synthesis and cell division and the formation of anticancer metabolites. Spallholz pays particular attention to the fact that catalytic redox selenium metabolites are formed by selenium metabolism which modulates the mitochondrial redox equilibrium and induces apoptosis in the cancer cells which have lost this regulating ability. (29)

            The Ganther group has shown that that selenium compounds “are able not only to arrest growth of cancer cells, but also to induce apoptosis.” (30)

            As Reilly points out in a review of the mechanisms for the anti-cancer actions of selenium, “This is a highly significant observation. Apoptosis, or as it is often called, programmed cell death, is a normal event at the end of the life cycle of most cells, except brain, cardiac and cancer cells. Cancer cells are normal cells that have been ‘immortalized’ and continue to divide, because they have lost the restraints imposed by the cell’s normal life cycle. The controlling factor for the induction of cellular apoptosis is the mitochondrion. Certain drugs, proteins and event signals outside the cell that produce changes in the integrity of the cellular mitochondria, induce apoptosis. Selenium compounds are known to cause mitochondrial swelling, a precursor event to apoptosis.” (8)

            Reilly also states, “Selenium is essential for optimal immune function, and stimulation of the immune system can be brought about by selenium supplementation. Experiments with mice have shown that selenium supplementation enhances the cellular immune response of the T-cell and the NK cell systems. In humans, stimulation with both vitamin E and selenium is believed to enhance all aspects of the immune system, through stimulation of interleukins and other associated T-cell genes.” (8)  Also see (31)

                        Another selenoprotein involved in the protection offered by selenium is thioredoxin reductase 1 (TR1). TR1 is the best-characterized isoform of the TR family of selenium-containing proteins. Much of the biological function of TR1 is attributed to its role as a reductant of the protein thioredoxin (TRx). Both TR and TRx are critical for redox control at the cellular level; together, they are involved in several biologic processes including antioxidant defense, cell proliferation, and inhibition of apoptosis. Although the components of the TR-TRx system have been reported to be over-expressed in cancer vs. normal cells, they may also play an important regulatory role in the function of p53, a tumor suppressor gene that is either deleted or suppressed in several human cancers. In this regard, it may also be significant that elevated p53 expression was correlated with lower TR positivity in breast tumor tissue.


            Rayman comments on the combined actions of selenoproteins and selenium metabolites in her 2005 review of selenium in cancer prevention (32) “As the level of selenium that appears to be required for optimal effect is higher than that previously understood to be required to maximize the activity of selenoenzymes, the question has been raised as to whether selenoproteins are involved in the anti-cancer process. However, recent evidence showing an association between selenium, reduction of DNA damage and oxidative stress together with data showing an effect of selenoprotein genotype on cancer risk implies that selenoproteins are indeed implicated. The likelihood of simultaneous and consecutive effects at different cancer stages still allows an important role for anti-cancer selenium metabolites such as methyl selenol formed from g-glutamyl-selenomethyl-SeCys and selenomethyl-SeCys, components identified in certain plants and selenium-enriched yeast that have anti-cancer effects.


            There is evidence that the cancer-preventing effect of dietary selenium is dependent on the metabolic production of methylated selenium metabolites. This effect is independent of other selenium effects such as by selenoproteins (11).


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