Doxorubicin-induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen. Role of reactive oxygen and nitrogen species

摘要: Doxorubicin (DOX) is a broad spectrum anthracycline antibiotic used to treat variety of cancers. Redox activation DOX form reactive oxygen species has been implicated in DOX-induced cardiotoxicity. In this work we investigated apoptosis cultured bovine aortic endothelial cells and cardiomyocytes isolated from adult rat heart. Exposure or myocytes submicromolar levels induced significant as measured by DNA fragmentation terminal deoxynucleotidyltransferase-mediated nick-end labeling assays. Pretreatment with 100 microm nitrone spin traps, N-tert-butyl-alpha-phenylnitrone (PBN) alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) dramatically inhibited apoptosis. Ebselen (20-50 microm), glutathione peroxidase mimetic, also significantly (0.5-1 microm) inactivated mitochondrial complex I superoxide-dependent mechanism. PBN (100 POBN ebselen (50 restored activity. These compounds caspase-3 cytochrome c release. DOX-treated cells. We conclude that traps inhibit the apoptotic signaling mechanism antiapoptotic may be linked part inhibition formation scavenging hydrogen peroxide. Therapeutic strategies mitigate cardiotoxicity should reexamined light these emerging mechanisms antioxidants.