title: Combined treatment with peroxisome proliferator-activated receptor (PPAR) gamma ligands and gamma radiation induces apoptosis by PPARγ-independent up-regulation of reactive oxygen species-induced deoxyribonucleic acid damage signals in non-small cell lung cancer cells.
abstract: OBJECTIVE
  To investigate possible radiosensitizing activities of the well-known peroxisome proliferator-activated receptor (PPAR)γ ligand ciglitazone and novel PPARγ ligands CAY10415 and CAY10506 in non-small cell lung cancer (NSCLC) cells.
  
  
  METHODS
  Radiosensitivity was assessed using a clonogenic cell survival assay. To investigate the mechanism underlying PPARγ ligand-induced radiosensitization, the subdiploid cellular DNA fraction was analyzed by flow cytometry. Activation of the caspase pathway by combined PPARγ ligands and γ-radiation treatment was detected by immunoblot analysis. Reactive oxygen species (ROS) were measured using 2,7-dichlorodihydrofluorescein diacetate and flow cytometry.
  
  
  RESULTS
  The 3 PPARγ ligands induced cell death and ROS generation in a PPARγ-independent manner, enhanced γ-radiation-induced apoptosis and caspase-3-mediated poly (ADP-ribose) polymerase (PARP) cleavage in vitro. The combined PPARγ ligand/γ-radiation treatment triggered caspase-8 activation, and this initiator caspase played an important role in the combination-induced apoptosis. Peroxisome proliferator-activated receptor-γ ligands may enhance the γ-radiation-induced DNA damage response, possibly by increasing γ-H2AX expression. Moreover, the combination treatment significantly increased ROS generation, and the ROS scavenger N-acetylcysteine inhibited the combined treatment-induced ROS generation and apoptotic cell death.
  
  
  CONCLUSIONS
  Taken together, these results indicated that the combined treatment of PPARγ ligands and γ-radiation synergistically induced DNA damage and apoptosis, which was regulated by ROS.
authors: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors: Eun Jong
authors: EJ
authors: Han
authors: Chang-Nim
authors: CN
authors: Im
authors: Seon Hwa
authors: SH
authors: Park
authors: Eun-Yi
authors: EY
authors: Moon
authors: Sung Hee
authors: SH
authors: Hong
mesh_terms: D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D004249:DNA Damage; D005452:Fluoresceins; D005720:Gamma Rays / Q000627:therapeutic use; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D047495:PPAR gamma / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay / Q000379:methods
chemical_list: C109098:2,7-dihydrodichlorofluorescein diacetate; C580959:CAY10415; C580960:CAY10506; D005452:Fluoresceins; C468783:H2AX protein, human; D006657:Histones; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053181:Caspase 8; C039671:ciglitazone