Clinical
chemoprevention trials of
lung cancer have been somewhat disappointing and the development of highly effective chemopreventive agents is urgently needed. We previously showed that the organoselenium
1,4-phenylenebis(methylene)selenocyanate (p-XSC) is a potent chemopreventive agent in numerous preclinical animal models including a lung
tumor model that employs
carcinogens found in tobacco
smoke. The goal of this study is to define molecular targets that will be highly promising in the design of future
chemoprevention trials of
non-small cell lung cancer (NSCLC), which is by far the most common type of
lung cancer cases. In the present investigation, we showed that p-XSC at several doses (2.5, 5, 10 and 20 microM) including physiological levels (2.5-5.0 microM) of
selenium is capable of inhibiting cell growth in a dose-dependent manner and inducing apoptosis in three NSCLC cells (NCI-H460, NCI-1299 and A549). To clarify the mechanism involved at the molecular level, we focused only on NCI-460 cells and examined the effects of p-XSC on markers that are known to be critical in the development of NSCLC. Using western blot analysis, we showed that p-XSC reduced the expression of
cyclooxygenase-2 (COX-2) and
phospholipase A2 (PLA2); although p-XSC inhibited both Akt and p-Akt but its effect was not significant. Using
cDNA microarray approach (3800 genes per array) we found that p-XSC upregulates 22 genes by > or = 2-fold while downregulates 13 genes by < or = 0.5-fold; these altered genes include transcriptional
factors, growth factors and those involved in
xenobiotic metabolism as well as pro- and anti-apoptotic genes. Expression of selected genes was confirmed by RT-PCR; p-XSC reduced the levels of COX-2, PLA2,
NF-kappaB and
Cyclin D1 but enhanced the levels of
glutathione peroxidase-5. Collectively, the results of this study showed that p-XSC alters several molecular markers in a manner that can account for its inhibitory effect of cell growth and induction of apoptosis; therefore, p-XSC may be considered a promising candidate for clinical
chemoprevention of NSCLC.