Trametinib, a MEK1/2 Inhibitor, Protects Mice from Cisplatin- and Noise-Induced Hearing Loss

被引:0
|
作者
Lutze, Richard D. [1 ]
Ingersoll, Matthew A. [1 ]
Kelmann, Regina G. [1 ]
Teitz, Tal [1 ,2 ]
机构
[1] Creighton Univ, Sch Med, Dept Pharmacol & Neurosci, Omaha, NE 68178 USA
[2] Scintillon Res Inst, San Diego, CA 92121 USA
基金
美国国家卫生研究院;
关键词
MAPK pathway; MEK1/2; trametinib; hearing protection; drug repurposing; oral delivery; cisplatin-induced hearing loss; noise-induced hearing loss; SUPPORTING CELLS; MECHANISMS; PATHWAY; ACTIVATION; DEATH; ERK;
D O I
10.3390/ph17060735
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Hearing loss is one of the most common types of disability; however, there is only one FDA-approved drug to prevent any type of hearing loss. Treatment with the highly effective chemotherapy agent, cisplatin, and exposure to high-decibel noises are two of the most common causes of hearing loss. The mitogen-activated protein kinase (MAPK) pathway, a phosphorylation cascade consisting of RAF, MEK1/2, and ERK1/2, has been implicated in both types of hearing loss. Pharmacologically inhibiting BRAF or ERK1/2 is protective against noise- and cisplatin-induced hearing loss in multiple mouse models. Trametinib, a MEK1/2 inhibitor, protects from cisplatin-induced outer hair cell death in mouse cochlear explants; however, to the best of our knowledge, inhibiting MEK1/2 has not yet been shown to be protective against hearing loss in vivo. In this study, we demonstrate that trametinib protects against cisplatin-induced hearing loss in a translationally relevant mouse model and does not interfere with cisplatin's tumor-killing efficacy in cancer cell lines. Higher doses of trametinib were toxic to mice when combined with cisplatin, but lower doses of the drug were protective against hearing loss without any known toxicity. Trametinib also protected mice from noise-induced hearing loss and synaptic damage. This study shows that MEK1/2 inhibition protects against both insults of hearing loss, as well as that targeting all three kinases in the MAPK pathway protects mice from cisplatin- and noise-induced hearing loss.
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页数:17
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