Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Department of Hearing and Speech Science, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Department of Hearing and Speech Science, Sun Yat-sen University, Guangzhou, China.
Toxicol Lett. 2020 Oct 1;331:1-10. doi: 10.1016/j.toxlet.2020.04.005. Epub 2020 May 16.
Cisplatin is a well-known and commonly used chemotherapeutic agent. However, cisplatin-induced ototoxicity limits its clinical use. Previous studies have shown an important role of reactive oxygen species (ROS) accumulation in the pathogenesis of cisplatin-induced ototoxicity. In many cell types, the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE) protect against oxidative stress by suppressing ROS. Here our results showed that cisplatin injury reduced Nrf2 expression and inhibited Nrf2 translocation in HEI-OC1 cells and Nrf2 activator tert-butylhydroquinone (TBHQ) rescued hair cells from cisplatin induced apoptosis by suppressing the total cellular ROS accumulation. Moreover, we found that decreased ROS accumulation induced by TBHQ didn't depend on mitochondrial derived ROS production, indicating that Nrf2 activation alleviated cisplatin induced oxidative stress and apoptosis through mitochondrial-independent ROS production. Therefore, we provide a potential strategy of prevention and treatment for cisplatin-induced ototoxicity by Nrf2 activation. In conclusion, Nrf2 activation protects auditory hair cells from cisplatin-induced ototoxicity through suppressing the total cellular ROS levels which arise from sources other than mitochondria.
顺铂是一种众所周知且常用的化疗药物。然而，顺铂诱导的耳毒性限制了其临床应用。先前的研究表明，活性氧（ROS）积累在顺铂诱导的耳毒性发病机制中起重要作用。在许多细胞类型中，转录因子，红细胞衍生 2 相关因子 2（Nrf2）和抗氧化反应元件（ARE）通过抑制 ROS 来保护细胞免受氧化应激。在这里，我们的结果表明，顺铂损伤降低了 HEI-OC1 细胞中 Nrf2 的表达并抑制了 Nrf2 的易位，而 Nrf2 激活剂叔丁基对苯二酚（TBHQ）通过抑制总细胞 ROS 积累，挽救了毛细胞免受顺铂诱导的细胞凋亡。此外，我们发现 TBHQ 诱导的 ROS 积累减少不依赖于线粒体来源的 ROS 产生，表明 Nrf2 激活通过线粒体非依赖性 ROS 产生减轻顺铂诱导的氧化应激和细胞凋亡。因此，我们通过 Nrf2 激活为顺铂诱导的耳毒性提供了一种潜在的预防和治疗策略。总之，Nrf2 激活通过抑制来自线粒体以外的源的总细胞 ROS 水平来保护听觉毛细胞免受顺铂诱导的耳毒性。
