CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss

Tal Teitz, Jie Fang, Asli N. Goktug, Justine D. Bonga, Shiyong Diao, Robert A. Hazlitt, Luigi Iconaru, Marie Morfouace, Duane Currier, Yinmei Zhou, Robyn A. Umans, Michael R. Taylor, Cheng Cheng, Jaeki Min, Burgess Freeman, Junmin Peng, Martine F. Roussel, Richard Kriwacki, R. Kiplin Guy, Taosheng ChenJian Zuo

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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 noiseinduced 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.

Original languageEnglish
Pages (from-to)1187-1203
Number of pages17
JournalJournal of Experimental Medicine
Volume215
Issue number4
DOIs
StatePublished - Apr 1 2018

Bibliographical note

Funding Information:
We thank Tetsuji Yamashita for sharing unpublished single-cell RNA sequencing results; Wilson Clements for providing fish; Amy Funk, Chandra Savage, Gregory Charlton, Richard Rahija, and Tiffani Rogers for assistance in the rat studies; Alex Salt and Zoran Rankovic for advice; Keith A. Laycock for scientific editing; and members of the Zuo laboratory for discussions. This work was supported by the National Institutes of Health (grants 2R01DC006471, 1R01DC015010-01A1, 1R01DC015444-01, 1R21DC013879-01 to J. Zuo; CA096832 to M.F. Roussel; R35GM118041 to T. Chen; and P30CA21765 to St. Jude's Children Research Hospital), by ALS AC, and by the Office of Naval Research (grants N000140911014, N000141210191, N000141210775, and N000141612315 to J. Zuo)

Publisher Copyright:
© 2018 Teitz et al.

ASJC Scopus subject areas

  • Medicine (all)

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