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First published on October 2, 2007; DOI: 10.1124/mol.107.040873

0026-895X/08/7301-119-127$20.00
Mol Pharmacol 73:119-127, 2008

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Peroxide Is a Key Mediator of Bcl-2 Down-Regulation and Apoptosis Induction by Cisplatin in Human Lung Cancer Cells

Liying Wang, Pithi Chanvorachote, David Toledo, Christian Stehlik, Robert R. Mercer, Vincent Castranova, and Yon Rojanasakul

Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia (L.Y., R.R.M., V.C.); Department of Physiology, Chulalongkorn University, Bangkok, Thailand (P.C.); Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia (D.T., Y.R.); and Division of Rheumatology, Northwestern University, Chicago, Illinois (C.S.)

Susceptibility to apoptosis is an essential prerequisite for successful eradication of tumor cells by chemotherapy. Consequently, resistance to apoptosis has been established as one of the mechanisms responsible for the failure of therapeutic approaches in many types of cancers. In the present study, we investigated the susceptibility of human lung cancer H460 cells to apoptotic cell death induced by cisplatin and determined its regulatory mechanisms. Treatment of the cells with cisplatin induced rapid generation of multiple oxidative species and a concomitant increase in apoptotic cell death. Apoptosis induced by cisplatin was mediated through the mitochondrial death pathway, which requires caspase-9 activation and is regulated by Bcl-2. Cisplatin induced down-regulation of Bcl-2 through a process that involves dephosphorylation and ubiquitination of the protein, which facilitates its degradation by proteasome. This down-regulation was inhibited by antioxidant enzymes catalase and glutathione peroxidase (H2O2 scavenger), but not by superoxide dismutase (Formula scavenger) or deferoxamine (OH· inhibitor). Electron spin resonance and flow cytometric analyses showed the formation of H2O2 along with Formula and OH· radicals after cisplatin treatment. H2O2 was generated in part by dismutation of Formula and served as a precursor for OH·. Together, our results indicate an essential role of H2O2 in the regulation of Bcl-2 and apoptotic cell death induced by cisplatin. Because aberrant expression of Bcl-2 has been associated with death resistance of cancer cells to chemotherapy, the results of this study could be used to aid the design of more effective strategies for cancer treatment.

Received August 13, 2007; accepted October 2, 2007

Address correspondence to: Dr. Yon Rojanasakul, West Virginia University, Department of Pharmaceutical Sciences, P.O. Box 9530, Morgantown, WV 26506. E-mail: yrojan{at}hsc.wvu.edu






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