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Int J Radiat Oncol Biol Phys. 2013 Apr 1;85(5):e239-48. doi: 10.1016/j.ijrobp.2012.11.040. Epub 2013 Jan 17.

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.

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1
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.

Abstract

PURPOSE:

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 AND MATERIALS:

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.

PMID:
23332223
DOI:
10.1016/j.ijrobp.2012.11.040
[Indexed for MEDLINE]
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