Chemoprevention of cancer by organoselenium compounds

A major research goal of our laboratories is the development of new organoselenium cancer chemopreventive agents with less toxicity compared to some of the historical selenium compounds, such as sodium selenite. Ideally, such agents would be employed to inhibit tumor development in different organs caused by a variety of chemical carcinogens, particularly those present in the human environment. A series of organoselenium compounds has been synthesized and evaluated for their chemopreventive efficacy in vivo. Parallel to these studies, short‐term in vitro and in vivo assays were employed to understand the mechanism of action and to rapidly evaluate their efficacy in eventual long‐term preclinical investigations. We demonstrated that one of the most effective of these organoselenium compounds, 1,4‐phenylenebis(methylene)selenocyanate (p‐XSC, Fig. 1), is capable of inhibiting tumors in the mammary glands, colon, and lung of laboratory animals. Dietary p‐XSC inhibited mammary tumor development induced by 7,12‐dimethylbenz(a)anthracene (DMBA) during both the initiation and post‐initiation phases of carcinogenesis in female CD rats. p‐XSC inhibited DMBA‐DNA adduct formation in the mammary glands. In collaboration with other laboratories, we demonstrated that p‐XSC inhibited thymidine kinase in mammary tumor cell lines derived from both humans and rats. Employing mammary carcinoma cell lines, p‐XSC was also shown to inhibit cell growth and induce a dose‐dependent increase in cell death by apoptosis. In these assays p‐XSC appears superior to selenite and to its sulfur analog, 1,4‐phenylenebis(methylene)thiocyanate. Dietary p‐XSC decreased colon tumor induction by azoxymethane in F344 rats during both phases of carcinogenesis. The effect of p‐XSC on colonic aberrant crypt multiplicity showed a similar trend. Colonic mucosal selenium‐dependent glutathione peroxidase activity was increased, and prostaglandin E₂ was reduced in animals fed the p‐XSC diet compared to animals fed the control diet. Dietary p‐XSC inhibited the formation of DNA adducts, as well as lung tumor development by the tobacco‐specific nitrosamine 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) in A/J mice, while selenite had no effect. These observations are important because smokers are exposed to NNK and could conceivably be protected against tumorigenesis by dietary supplements of effective organoselenium compounds. Collectively, these results indicate that p‐XSC and similar organoselenium compounds are capable of inhibiting tumors in mammary gland, colon, and lung of animals in model systems. Moreover, the results of short‐term bioassays described above are encouraging and could assist in the design of even better and less toxic organoselenium chemopreventive agents than p‐XSC for future application in preclinical assays and subsequently in human clinical intervention.