Necroptosis and Apoptosis Contribute to Cisplatin and Aminoglycoside Ototoxicity
Necroptosis and Apoptosis Contribute to Cisplatin and Aminoglycoside Ototoxicity
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DOI：
10.1523/jneurosci.1384-18.2019
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发表时间：
2019-04-10
影响因子：
5.3
通讯作者：
Shin, Jung-Bum
中科院分区：
文献类型：
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作者：
Ruhl, Douglas;Du, Ting-Ting;Shin, Jung-Bum
顺铂和氨基糖苷类药物的耳毒性副作用已经被广泛研究，但到目前为止还没有可用的治疗方法。感觉毛细胞在接触顺铂或氨基糖苷类药物时，会发生细胞凋亡和坏死。阻断这些细胞死亡途径在理论上具有治疗潜力，但在坏死情况下不完全保护和缺乏治疗靶点，阻碍了临床适用药物的开发。在过去的十年里，一种新的坏死形式，称为坏死性下垂，被确定为另一种细胞死亡途径。坏死性下垂不同于被动的坏死性细胞死亡，因为它遵循一个细胞程序，涉及受体相互作用蛋白激酶(RIPK)1和RIPK3。在这项研究中，我们在小鼠中使用药理学和遗传学干预来测试坏死性下垂和caspase-8介导的细胞凋亡对顺铂和氨基糖苷类耳毒性的相对贡献。我们发现，在体外，顺铂和氨基糖苷类药物的耳毒性只与细胞凋亡有关，而在体内，死亡性下垂和细胞凋亡是男女共同参与的。因此，使用药物化合物抑制坏死性下垂和细胞凋亡是改善氨基糖苷类药物和顺铂耳毒性的可行策略。
Ototoxic side effects of cisplatin and aminoglycosides have been extensively studied, but no therapy is available to date. Sensory hair cells, upon exposure to cisplatin or aminoglycosides, undergo apoptotic and necrotic cell death. Blocking these cell death pathways has therapeutic potential in theory, but incomplete protection and lack of therapeutic targets in the case of necrosis, has hampered the development of clinically applicable drugs. Over the past decade, a novel form of necrosis, termed necroptosis, was established as an alternative cell death pathway. Necroptosis is distinguished from passive necrotic cell death, in that it follows a cellular program, involving the receptor-interacting protein kinase (RIPK) 1 and RIPK3. In this study, we used pharmacological and genetic interventions in the mouse to test the relative contributions of necroptosis and caspase-8-mediated apoptosis toward cisplatin and aminoglycoside ototoxicity. Wefind that ex vivo, only apoptosis contributes to cisplatin and aminoglycoside ototoxicity, while in vivo, necroptosis as well as apoptosis are involved in both sexes. Inhibition of necroptosis and apoptosis using pharmacological compounds is thus a viable strategy to ameliorate aminoglycoside and cisplatin ototoxicity.