The Selenium Analog of the Chemopreventive Compound S,S'-(1,4-phenylenebis[1,2-ethanediyl])bisisothiourea is a Remarkable Inducer of Apoptosis and Inhibitor of Cell Growth in Human Non-small Cell Lung Cancer

Lung cancer continues to be the leading cause of cancer deaths throughout the world and conventional therapy remains largely unsuccessful. Although, chemoprevention is a plausible alternative approach to curb the lung cancer epidemic, clinically there are no effective chemopreventive agents. Thus, development of novel compounds that can target cellular and molecular pathways involved in the multistep carcinogenesis process is urgently needed. Previous studies have suggested that substitution of sulfur by selenium in established cancer chemopreventive agents may result in more effective analogs. Thus in the present study we selected the chemopreventive agent S,S'-(1,4-phenylenebis[1,2-ethanediyl])bisisothiourea (PBIT), also known to inhibit inducible nitric oxide synthase (iNOS), synthesized its selenium analog (Se-PBIT) and compared both compounds in preclinical model systems using non-small cell lung cancer (NSCLC) cell lines (NCI-H460 and A549); NSCLC is the most common histologic type of all lung cancer cases. Se-PBIT was found to be superior to PBIT as an inducer of apoptosis and inhibitor of cell growth. Se-PBIT arrested cell cycles at G1 and G2-M stage in both A549 and H460 cell lines. Although both compounds are weakly but equally effective inhibitors of iNOS protein expression and activity, only Se-PBIT significantly enhanced the levels of p53, p38, p27 and p21 protein expression, reduced levels of phospholipase A2 (PLA2) but had no effect on cyclooxygenase-2 (COX-2) protein levels; such molecular targets are involved in cell growth inhibition, induction of apoptosis and cell cycle regulation. The results indicate that Se-PBIT altered molecular targets that are involved in the development of human lung cancer. Although, the mechanisms that can fully account for these effects remain to be determined, the results are encouraging to further evaluate the chemopreventive efficacy of Se-PBIT against the development of NSCLC in a well-defined animal model.