Combined treatment with the Cox-2 inhibitor niflumic acid and PPARγ ligand ciglitazone induces ER stress/caspase-8-mediated apoptosis in human lung cancer cells

The present study was performed to investigate the possible combined use of the COX-2 Inhibitor niflumic acid and the PPARγ ligand ciglitazone and to elucidate the mechanisms underlying enhanced Apoptosis by this combination treatment in human lung Cancer cells. Combined niflumic acid-ciglitazone treatment synergistically induced apoptotic cell death, activated caspase-9, Caspase-3, and induced caspase-3-mediated PARP cleavage. The combination treatment also triggered Apoptosis through Caspase-8/Bid/Bax activation, and the inhibition of Caspase-8 suppressed Caspase-8/Bid activation, caspase-3-mediated PARP cleavage, and concomitant Apoptosis. In addition, combined niflumic acid-ciglitazone treatment significantly induced ER stress responses, and suppression of CHOP expression significantly attenuated the combined niflumic acid-ciglitazone treatment-induced activation of Caspase-8 and Caspase-3, and the subsequent apoptotic cell death, indicating a role of ER stress in Caspase-8 activation and Apoptosis. Interestingly, the pro-apoptotic effects of combined niflumic acid-ciglitazone treatment were realized through Cox-2- and PPARγ-independent mechanisms. Taken together, these results suggest that sequential ER stress and Caspase-8 activation are critical in combined niflumic acid-ciglitazone treatment-induced Apoptosis in human lung Cancer cells.