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.
Korea Institute of Radiological & Medical Sciences, Nowon-Gu, Seoul, Republic of Korea.
Byeong Mo
BM
Kim
Kyungah
K
Maeng
Kee-Ho
KH
Lee
Sung Hee
SH
Hong
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism; D009544:Niflumic Acid / Q000494:pharmacology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection
D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D009544:Niflumic Acid; D051546:Cyclooxygenase 2; D053181:Caspase 8; C039671:ciglitazone