PUBLICATION
CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss
- Authors
- 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., Guy, R.K., Chen, T., Zuo, J.
- ID
- ZDB-PUB-180309-2
- Date
- 2018
- Source
- The Journal of experimental medicine 215(4): 1187-1203 (Journal)
- Registered Authors
- Taylor, Michael R.
- Keywords
- none
- MeSH Terms
-
- Zebrafish
- Protein Kinase Inhibitors/therapeutic use*
- Mice, Knockout
- Indoles/pharmacology
- Indoles/therapeutic use
- Small Molecule Libraries/analysis
- Hair Cells, Auditory/drug effects
- Hair Cells, Auditory/pathology
- Mice, Inbred C57BL
- Cisplatin/adverse effects*
- Reactive Oxygen Species/metabolism
- Cytoprotection/drug effects
- Benzazepines/pharmacology
- Benzazepines/therapeutic use
- Hearing Loss, Noise-Induced/chemically induced*
- Hearing Loss, Noise-Induced/drug therapy*
- Lateral Line System/drug effects
- Lateral Line System/pathology
- Animals
- Drug Resistance
- Rats
- Mitochondria/metabolism
- Cell Death/drug effects
- Germ Cells/metabolism
- Cyclin-Dependent Kinase 2/antagonists & inhibitors*
- Cyclin-Dependent Kinase 2/metabolism
- Cell Line, Tumor
- PubMed
- 29514916 Full text @ J. Exp. Med.
Citation
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., Guy, R.K., Chen, T., Zuo, J. (2018) CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. The Journal of experimental medicine. 215(4):1187-1203.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping