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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

 Byeong Mo Kim  ;  Kyungah Maeng  ;  Kee-Ho Lee  ;  Sung Hee Hong 
 CANCER LETTERS, Vol.300(2) : 134-144, 2011 
Journal Title
Issue Date
Antineoplastic Combined Chemotherapy Protocols/pharmacology* ; Apoptosis/drug effects* ; Blotting, Western ; Caspase 8/metabolism ; Cell Line, Tumor ; Cell Separation ; Cyclooxygenase 2/drug effects ; Cyclooxygenase 2/metabolism ; Drug Synergism ; Endoplasmic Reticulum/drug effects ; Endoplasmic Reticulum/metabolism ; Flow Cytometry ; Humans ; Ligands ; Lung Neoplasms*/metabolism ; Niflumic Acid/pharmacology* ; PPAR gamma/antagonists & inhibitors ; Reverse Transcriptase Polymerase Chain Reaction ; Thiazolidinediones/pharmacology* ; Transfection
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.
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5. Research Institutes (연구소) > Yonsei Integrative Research Institute for Cerebral & Cardiovascular Disease (뇌심혈관질환융합연구사업단) > 1. Journal Papers
Yonsei Authors
Kim, Byeong Mo(김병모) ORCID logo https://orcid.org/0000-0002-0582-3132
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