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Posted on Mar 23, 2018, 3 p.m.
Inhibiting an enzyme called cyclin-dependent kinase 2 has been shown to protect mice and rat models from noise and drug induced hearing loss by researchers at St. Jude Children’s Hospital, suggesting that CDK2 inhibitors may prevent inner ear cell death as published in the Journal Of Experimental Medicine.
It is estimated by the World Health Organization that 360 million people worldwide suffer from hearing loss caused by congenital defect or other factors including use of certain medicines, infectious disease, and exposure to excessive noise. Currently there are no known FDA approved drugs to be used in the prevention of hearing loss available.
Over 4000 drugs were screened for ability to protect cochlear cells from chemotherapy agent cisplatin which causes irreversible hearing loss in 70% of the patients used to fight cancers in. Multiple compounds were identified by the researchers with the ability to protect cochlear cells from cisplatin, several of which are currently approved for use in treatment of other conditions. 3 of the most effective compounds were inhibitors of an enzyme called cyclin-dependent kinase 2. Kenpaullone is one of those inhibitors that was observed to be more effective than 4 other compounds that are currently in clinical trials to treat hearing loss.
Cisplatin induced hearing loss was observed to be protected in mice and rats with kenpaullone injection into the middle ear, appearing to protect hair cells by preventing cyclin-dependent kinase 2 from stimulating the production of toxic reactive oxygen species from the cell mitochondria. Kenpaullone also was observed to protect the hearing from noise as loud as 100 dB. Meaning kenpaullone may have significant clinical applications in the treatment of hearing loss.
Kenpaullone provided a robust protection conferred by a single one time local delivery suggesting cyclin-dependent kinase 2 inhibitors may transform clinical prevention and treatment of cisplatin and noise induced hearing loss in patients. Modifications of treatment regimens, optimization of delivery methods, and structural modifications of the compounds could ensure greater results with cyclin-dependent kinase 2 inhibitors to be used in the treatment of hearing loss in humans.
Materials provided by Rockefeller University Press.
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Journal Reference:
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. CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. The Journal of Experimental Medicine, 2018; jem.20172246 DOI: 10.1084/jem.20172246
