The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

Background and purpose: Ototoxicity is a known adverse effect of cisplatin (CDDP). Since apoptosis is involved in the development of some pathological conditions associated with the administration of anticancer drugs, we examined, using immunohistochemical and electrophysiological techniques, the apoptotic changes in the cochlea of Sprague‐Dawley (SD) rats after an injection of CDDP (5 mgkg‐1 body weight). Experimental approach: Luciferase assays were used to determine the different caspase activities and ATP levels in protein extracts of whole cochleae. The expression of several apoptotic‐related proteins was measured by means of Western blotting. These analyses were performed 2, 7 and 30 days after the CDDP injection. The auditory brain stem response was obtained before and at the different times after the injection of CDDP, before the animals were killed. Key results: CDDP significantly increased the levels of caspase‐3/7 activity and active caspase‐3 protein expression and caspase‐3 immunofluorescence staining, caspase‐9 activity, and Bax protein expression but decreased Bcl‐2 protein expression within the rat cochleae. Threshold shifts were significantly elevated 2 days after CDDP treatment. Conclusions and implications: These findings support the hypothesis that cisplatin‐related apoptosis evokes an intrinsic pathway of pro‐apoptotic signalling within the rat cochleae. Thus, selective inhibition of the sequence of events involved in the intrinsic apoptotic pathway could provide a strategy to minimize cisplatin‐induced ototoxicity. British Journal of Pharmacology (2007) 152, 1012–1020; doi:10.1038/sj.bjp.0707405; published online 1 October 2007