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.