APAF-1 inhibition reduces cisplatin-induced hearing loss

Abstract

Cisplatin is an essential chemotherapeutic agent in the treatment of many cancers, especially in childhood cancers. Hearing loss is a common side-effect associated to cisplatin chemotherapy. Cisplatin induces apoptosis in inner ear hair cells by an APAF-1 dependentpathway. Here, we evaluated in vitro and in vivo the ability of an APAF-1 selective inhibitor, on the prevention of cisplatin-induced hearing loss. Our results showed that APAF-1 inhibitor i) bloked the formation of the apoptosome complex in vitro; ii) decreased cytochrome C release and caspase-3 activation, and increased HEIOC1 cells survival after cisplatin administration; and iii) induced a dose-dependent otoprotective effect after intratympanic administration, in rats receiving systemic cisplatin. All these data suggest that APAF-1 is an interesting molecular target and point APAF-1 inhibitors as promising putative potential therapeutic drug to prevent cisplatin-induced hearing loss.