Abstract
Hearing loss caused by aging, noise, cisplatin toxicity, or other insults affects 360 million people worldwide, but there are no Food and Drug Administration-approved drugs to prevent or treat it. We screened 4,385 small molecules in a cochlear cell line and identified 10 compounds that protected against cisplatin toxicity in mouse cochlear explants. Among them, kenpaullone, an inhibitor of multiple kinases, including cyclin-dependent kinase 2 (CDK2), protected zebrafish lateral-line neuromasts from cisplatin toxicity and, when delivered locally, protected adult mice and rats against cisplatin- and noise-induced hearing loss. CDK2-deficient mice displayed enhanced resistance to cisplatin toxicity in cochlear explants and to cisplatin- and noise-induced hearing loss in vivo. Mechanistically, we showed that kenpaullone directly inhibits CDK2 kinase activity and reduces cisplatin-induced mitochondrial production of reactive oxygen species, thereby enhancing cell survival. Our experiments have revealed the proapoptotic function of CDK2 in postmitotic cochlear cells and have identified promising therapeutics for preventing hearing loss.
Highlights
More than 360 million people worldwide suffer from hearing loss caused by noise, chemotherapy, antibiotics, viral infections, genetic predisposition, or aging (World Health Organization, 2017)
The neuromasts consist of hair cells (HCs) that are subject to cisplatin and antibiotic toxicity, a feature that has been exploited successfully for in vivo screening of protective compounds (Coffin et al, 2010); the effectiveness of the compounds identified in this model has yet to be validated in mammals
Caspase-3/7 activity was chosen as the endpoint for measuring cell death in an assay that quantifies a luminescent product derived by the specific cleavage of a caspase-3/7 substrate (Caspase-Glo 3/7 reagent; Fig. S1 A); caspase-3/7 activity was defined as 100% in the cells treated with cisplatin alone and as 0% in cells not treated with cisplatin (Fig. 1 A)
Summary
More than 360 million people worldwide suffer from hearing loss caused by noise, chemotherapy, antibiotics, viral infections, genetic predisposition, or aging (World Health Organization, 2017). Genomic loci have been identified that predispose pediatric patients with brain tumors to hearing loss when treated with cisplatin (Ross et al, 2009; Xu et al, 2015). These genomic loci can help identify the specific patients to whom the protective drugs should be given, individualizing the treatment. There are no Food and Drug Administration (FDA)–approved drugs that protect against noise-, cisplatin-, or antibiotic-induced or age-related hearing loss (Oishi and Schacht, 2011; El Kechai et al, 2015; Müller and Barr-Gillespie, 2015). The neuromasts consist of hair cells (HCs) that are subject to cisplatin and antibiotic toxicity, a feature that has been exploited successfully for in vivo screening of protective compounds (Coffin et al, 2010); the effectiveness of the compounds identified in this model has yet to be validated in mammals
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