Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL 62794-9629, USA.
Cell Death Dis. 2011 Jul 21;2(7):e180. doi: 10.1038/cddis.2011.63.
Cisplatin is widely used for treating various solid tumors. However, this drug produces dose-limiting ototoxicity and nephrotoxicity, which significantly reduce the quality of life of cancer patients. While nephrotoxicity could be alleviated by diuresis, there is currently no approved treatment for hearing loss. Previous studies show that the ROS and inflammation are major contributors to cisplatin-induced hearing loss. In this study, we show that ROS trigger the inflammatory process in the cochlea by activating signal transducer and activator of transcription-1 (STAT1). Activation of STAT1 activation was dependent on ROS generation through NOX3 NADPH oxidase, knockdown of which by siRNA reduced STAT1 activation. Moreover, STAT1 siRNA protected against activation of p53, reduced apoptosis, reduced damage to OHCs and preserved hearing in rats. STAT1 siRNA attenuated the increase in inflammatory mediators, such as TNF-α, inhibition of which protected cells from cisplatin-mediated apoptosis. Finally, we showed that trans-tympanic administration of etanercept, a TNF-α antagonist, protected against OHC damage and cisplatin-induced hearing loss. These studies suggest that controlling inflammation by inhibition of STAT1-dependent pathways in the cochlea could serve as an effective approach to treat cisplatin ototoxicity and improve the overall quality of life for cancer patients.
顺铂被广泛用于治疗各种实体瘤。然而，这种药物会产生剂量限制的耳毒性和肾毒性，这会显著降低癌症患者的生活质量。虽然利尿可以减轻肾毒性，但目前尚无针对听力损失的批准治疗方法。先前的研究表明，ROS 和炎症是顺铂诱导的听力损失的主要原因。在这项研究中，我们表明 ROS 通过激活信号转导和转录激活因子 1（STAT1）触发耳蜗中的炎症过程。STAT1 的激活依赖于通过 NOX3 NADPH 氧化酶产生的 ROS，通过 siRNA 敲低该酶可减少 STAT1 的激活。此外，STAT1 siRNA 可防止 p53 的激活、减少细胞凋亡、减少 OHC 的损伤并保护大鼠的听力。STAT1 siRNA 可减轻 TNF-α 等炎症介质的增加，抑制这些介质可防止细胞发生顺铂介导的凋亡。最后，我们表明，经鼓膜给予 TNF-α 拮抗剂依那西普可防止 OHC 损伤和顺铂引起的听力损失。这些研究表明，通过抑制耳蜗中 STAT1 依赖性途径来控制炎症可能是治疗顺铂耳毒性和提高癌症患者整体生活质量的有效方法。
