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 Chen; Jian Zuo

doi:10.1084/jem.20172246

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 journal › Article › peer-review

60 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 language	English
Pages (from-to)	1187-1203
Number of pages	17
Journal	Journal of Experimental Medicine
Volume	215
Issue number	4
DOIs	https://doi.org/10.1084/jem.20172246
State	Published - 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We thank Tetsuji Yamashita for sharing unpublished single-cell RNA sequencing results; Wilson Clements for providing fish; Amy Funk, Chandra Savage, Gregory Charlton, Richard Rahija, and Tiffani Rogers for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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10.1084/jem.20172246

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Teitz, T., Fang, J., Goktug, A. N., Bonga, J. D., Diao, S., Hazlitt, R. A., Iconaru, L., Morfouace, M., Currier, D., Zhou, Y., Umans, R. A., Taylor, M. R., Cheng, C., Min, J., Freeman, B., Peng, J., Roussel, M. F., Kriwacki, R., Kiplin Guy, R., ... Zuo, J. (2018). CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. Journal of Experimental Medicine, 215(4), 1187-1203. https://doi.org/10.1084/jem.20172246

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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.",

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

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: {\textcopyright} 2018 Teitz et al.",

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Teitz, T, Fang, J, Goktug, AN, Bonga, JD, Diao, S, Hazlitt, RA, Iconaru, L, Morfouace, M, Currier, D, Zhou, Y, Umans, RA, Taylor, MR, Cheng, C, Min, J, Freeman, B, Peng, J, Roussel, MF, Kriwacki, R, Kiplin Guy, R, Chen, T & Zuo, J 2018, 'CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss', Journal of Experimental Medicine, vol. 215, no. 4, pp. 1187-1203. https://doi.org/10.1084/jem.20172246

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T1 - CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss

AU - Teitz, Tal

AU - Fang, Jie

AU - Goktug, Asli N.

AU - Bonga, Justine D.

AU - Diao, Shiyong

AU - Hazlitt, Robert A.

AU - Iconaru, Luigi

AU - Morfouace, Marie

AU - Currier, Duane

AU - Zhou, Yinmei

AU - Umans, Robyn A.

AU - Taylor, Michael R.

AU - Cheng, Cheng

AU - Min, Jaeki

AU - Freeman, Burgess

AU - Peng, Junmin

AU - Roussel, Martine F.

AU - Kriwacki, Richard

AU - Kiplin Guy, R.

AU - Chen, Taosheng

AU - Zuo, Jian

N1 - 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.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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.

AB - 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.

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DO - 10.1084/jem.20172246

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JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 4

ER -

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

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