Peroxide is a key mediator of Bcl-2 down-regulation and apoptosis induction by cisplatin in human lung cancer cells. Mol Pharmacol 73

Susceptibility to apoptosis is an essential prerequisite for suc-cessful eradication of tumor cells by chemotherapy. Conse-quently, resistance to apoptosis has been established as one of the mechanisms responsible for the failure of therapeutic ap-proaches 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 in-duced 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 ubiq