Department of Surgery, Division of Otolaryngology, Southern Illinois University, School of Medicine, Springfield, IL 62794-9649, USA.
Cell Mol Life Sci. 2012 Jul;69(14):2429-34. doi: 10.1007/s00018-012-1016-3. Epub 2012 May 5.
Cisplatin is a widely used chemotherapeutic agent that causes significant hearing loss. Previous studies have shown that cisplatin exposure is associated with increase in reactive oxygen species (ROS) in the cochlea. The inner ear expresses a unique isoform of NADPH oxidase, NOX3. This enzyme may be the primary source of ROS generation in the cochlea. The knockdown of NOX3 by pretreatment with siRNA prevented cisplatin ototoxicity, as demonstrated by preservation of hearing thresholds and inner ear sensory cells. Trans-tympanic NOX3 siRNA reduced the expression of NOX3 and biomarkers of cochlear damage, including transient receptor vanilloid 1 (TRPV1) channel and kidney injury molecule-1 (KIM-1) in cochlear tissues. In addition, siRNA against NOX3 reduced apoptosis as demonstrated by TUNEL staining, and prevented the increased expression of Bax and abrogated the decrease in Bcl2 expression following cisplatin administration. Trans-tympanic administration of siRNA directed against NOX3 may provide a useful method of attenuating cisplatin ototoxicity. In this paper, we review recent publications dealing with the role of NOX3 in ototoxicity and the effects of siRNA against cisplatin-induced hearing loss.
顺铂是一种广泛应用的化疗药物，会导致严重的听力损失。先前的研究表明，顺铂暴露会导致耳蜗中活性氧（ROS）的增加。内耳表达一种独特的 NADPH 氧化酶同工型，即 NOX3。这种酶可能是耳蜗中 ROS 产生的主要来源。用 siRNA 预处理进行的 NOX3 敲低可防止顺铂耳毒性，这表现在听力阈值和内耳感觉细胞的保留上。经鼓室给予的 NOX3 siRNA 可降低 NOX3 的表达和耳蜗损伤的生物标志物，包括耳蜗组织中的瞬时受体香草酸 1（TRPV1）通道和肾损伤分子 1（KIM-1）。此外，siRNA 对 NOX3 的抑制作用如 TUNEL 染色所示，可减少细胞凋亡，并防止顺铂给药后 Bax 的表达增加和 Bcl2 表达的减少。针对 NOX3 的 siRNA 的经鼓室给药可能为减轻顺铂耳毒性提供一种有用的方法。在本文中，我们综述了最近涉及 NOX3 在耳毒性中的作用以及针对顺铂诱导的听力损失的 siRNA 作用的出版物。
