In silico transcriptomics identifies FDA-approved drugs and biological pathways for protection against cisplatin-induced hearing loss

Abstract

Acquired hearing loss is a major health problem that affects 5-10% of the world population. However, there are no FDA-approved drugs for the treatment or prevention of hearing loss. Employing the Connectivity Map (CMap) that contains >54,000 compounds, we performed an unbiased in silico screen using the transcriptomic profiles of cisplatin-resistant and -sensitive cancer cell lines. Pathway enrichment analysis identified gene-drug targets for which 30 candidate drugs were selected with potential to confer protection against cisplatin-induced ototoxicity. In parallel, transcriptomic analysis of a cisplatin-treated cochlear-derived cell line identified common enriched pathway targets. We subsequently tested these top 30 candidate compounds, 15 (50%) of which are FDA-approved for other indications, and 26 (87%) of which were validated for their protective effects in either a cochlear-derived cell line or zebrafish lateral line neuromasts, thus confirming our in silico transcriptomic approach. Among these top compounds, niclosamide, a salicyanilide drug approved by the FDA for treating tapeworm infections for decades, protected from cisplatin- and noise-induced hearing loss in mice. Finally, niclosamide and ezetimibe (an Nrf2 agonist) exerted synergistic protection against cisplatin-ototoxicity in zebrafish, validating the Nrf2 pathway as part of niclosamide's mechanism of action. Taken together, employing the CMap, we identified multiple pathways and drugs against cisplatin ototoxicity and confirmed that niclosamide can effectively be repurposed as an otoprotectant for future clinical trials against cisplatin- and noise-induced hearing loss.

Approaches to Mitigate Mitochondrial Dysfunction in Sensorineural Hearing Loss

“…25 Niclosamide is another mitochondrial uncoupling small molecule that reduces mitochondrial membrane potential in cultured fibroblast cells and prevents noise or cisplatin-induced hair cell loss and restores elevated hearing thresholds in mice. 64,71 Several natural metabolites that induce mitophagy have a beneficial impact on hearing loss. For instance, Urolithin A, a natural food metabolite that is abundant in pomegranate, increases mitochondrial function and attenuated premature senescence in H 2 O 2 -induced auditory cells.…”