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

Cancer Lett. 2011 Jan 28;300(2):134-44. doi: 10.1016/j.canlet.2010.09.014. Epub 2010 Nov 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Ligands
  • PPAR gamma
  • Thiazolidinediones
  • Niflumic Acid
  • Cyclooxygenase 2
  • Caspase 8
  • ciglitazone