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 PPAR gamma 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 PPAR gamma-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 (C) 2010 Elsevier Ireland Ltd All rights reserved