title: Cisplatin-induced apoptosis in auditory cells: role of death receptor and mitochondrial pathways.
abstract: Cisplatin, a commonly used chemotherapeutic agent, has a major limitation due to its ototoxicity. Previous studies have shown that cisplatin induces apoptosis in auditory sensory cells, but the underlying mechanisms remain to be elucidated. In this study, cisplatin was found to induce apoptosis in a cochlear cell line, in a dose- and duration-dependent manner. Specific caspase assays revealed an early (6 h) but transient increase in caspase 8 activity, and a delayed (12 h) increase in caspase 9 activity. The enhanced caspase 8 activity was preceded by upregulation of p53 expression, and coincided with cleavage of Bid to its truncated form. This was followed temporally by activation and mitochondrial translocation of Bax, induction of mitochondrial permeability transition, release of cytochrome c into the cytosol, activation of caspase 9, and entry into the execution phase of apoptosis. Our results indicate the involvement of both the death receptor mechanisms as well as mitochondrial pathways in cisplatin-induced apoptosis of auditory cells in an in vitro model system.
authors.affiliation: Division of Nephrology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA. prasad.devarajan@chmcc.org
authors.forename: Prasad
authors.initials: P
authors.lastname: Devarajan
authors.forename: Michelle
authors.initials: M
authors.lastname: Savoca
authors.forename: M Patricia
authors.initials: MP
authors.lastname: Castaneda
authors.forename: Moon Soo
authors.initials: MS
authors.lastname: Park
authors.forename: Nora
authors.initials: N
authors.lastname: Esteban-Cruciani
authors.forename: Gilda
authors.initials: G
authors.lastname: Kalinec
authors.forename: Federico
authors.initials: F
authors.lastname: Kalinec
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000737:chemistry / Q000187:drug effects; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D003051:Cochlea / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D013997:Time Factors; D014018:Tissue Distribution; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein
chemical_list: D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins; D003574:Cytochrome c Group; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002945:Cisplatin