Cisplatin-induced apoptosis in auditory cells: Role of death receptor and mitochondrial pathways

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.