Substitution of sulfur by selenium in S,S’-(1,4-phenylenebis[1,2-ethanediyl])bisisothiourea (PBIT), an established iNOS inhibitor, significantly enhances the induction of apoptosis and p53 protein expression in human non-small cell lung cancer. Free

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Lung cancer is the leading cause of mortality in men and women. Smoking contributes to more than 90% of all deaths from lung cancer in men and to about 80% of all deaths from lung cancer in women. To reduce the lung cancer epidemic is to quit smoking; this has been and continues to be the ultimate goal of prevention. Dietary interventions or the use of chemopreventive agents can provide complementary approaches for lowering the lung cancer risk in ex-smokers, and possibly in active smokers. However, clinical chemoprevention trials of lung cancer using vitamins have been unsuccessful but the use of selenium appears to provide some protection against lung cancer. Although numerous agents including the organoselenium 1, 4-phenylenebis(methylene)selenocyanate (p-XSC) have been shown to inhibit tobacco carcinogens (e.g. NNK, B[a]p)-induced lung tumors in animal models, when administered continuously, there is an urgent need to develop selenium compounds that can be effective during the promotion/progression phases of lung carcinogenesis, i.e. agents that can be used in ex-smokers to reduce the lingering lung cancer risk that remains high for 5-10 years after cessation of the habit. Using preclinical model systems our current research efforts are aimed at developing novel chemopreventive organoselenium compounds as well as defining a molecular staging system that is highly promising in cancer chemoprevention. In the present study we used human non-small cell lung cancer (NSCLC) cells since it is by far the most common histologic type of all lung cancer cases. Our previous studies have examined the effect of p-XSC on several molecular markers that are known to be critical in the development of NSCLC. iNOS protein expression levels have been found to be elevated in lung cancer patients as well as levels of NO. Thus, we selected an established iNOS inhibitor which is a sulfur containing compound namely S,S’-(1,4-phenylenebis[1,2-ethanediyl])bisisothiourea (PBIT), synthesized its selenium analog, and compared both agents in NSCLC cell lines (NCI H460 and A549). Although PBIT and Se-PBIT showed similar inhibitory effects on iNOS protein expression and NO production, Se-PBIT was superior to PBIT as an inducer of apoptosis and inhibitor of cell proliferation. Furthermore only Se-PBIT significantly enhanced the levels of p53, p38, p27 and p21 protein expression. Since these molecular markers are known to regulate important cellular responses in the multi-step carcinogenesis process, our results indicate that Se-PBIT may be a promising agent against lung cancer and needs to be evaluated initially in preclinical animal models. Support NCI-CA70972