Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN.
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN.
J Exp Med. 2018 Apr 2;215(4):1187-1203. doi: 10.1084/jem.20172246. Epub 2018 Mar 7.
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.
年龄增长、噪声、顺铂毒性或其他因素引起的听力损失影响着全球 3.6 亿人，但目前还没有获得美国食品和药物管理局批准的药物来预防或治疗这种疾病。我们在耳蜗细胞系中筛选了 4385 种小分子，发现了 10 种能对抗顺铂毒性的化合物，这些化合物能保护小鼠耳蜗外植体免受顺铂毒性的影响。其中，多激酶抑制剂 kenpaullone，包括细胞周期蛋白依赖性激酶 2（CDK2），能保护斑马鱼侧线毛细胞免受顺铂毒性的影响，局部给药还能保护成年小鼠和大鼠免受顺铂和噪声引起的听力损失。CDK2 缺陷型小鼠在耳蜗外植体中对顺铂毒性的抵抗力增强，体内对顺铂和噪声引起的听力损失的抵抗力也增强。从机制上讲，我们发现 kenpaullone 能直接抑制 CDK2 激酶活性，减少顺铂诱导的线粒体活性氧的产生，从而提高细胞存活率。我们的实验揭示了 CDK2 在有丝分裂后耳蜗细胞中的促凋亡功能，并确定了有希望的预防听力损失的治疗方法。
