Cisplatin-induced ototoxicity: From signaling network to therapeutic targets

作者：Xilu Wang, Yingying Zhou, Dali Wang, Yi Wang, Zhaoyu Zhou, Xiulan Ma, Xiaofang Liu, Yaodong Dong · 发表于：Biomedicine & Pharmacotherapy · 年份：2022 · DOI：10.1016/j.biopha.2022.114045 · 被引用次数：141 · 研究领域：Hearing, Cochlea, Tinnitus, Genetics、Vestibular and auditory disorders、Ear and Head Tumors

Administration of cisplatin, a common chemotherapeutic drug, has an inevitable side effect of sensorineural hearing loss. The main etiologies are stria vascularis injury, spiral ganglion degeneration, and hair cell death. Over several decades, the research scope of cisplatin-induced ototoxicity has expanded with the discovery of the molecular mechanism mediating inner ear cell death, highlighting the roles of reactive oxygen species and transport channels for cisplatin uptake into inner ear cells. Upon entering hair cells, cisplatin disrupts organelle metabolism, induces oxidative stress, and targets DNA to cause intracellular damage. Recent studies have also reported the role of inflammation in cisplatin-induced ototoxicity. In this article, we preform a narrative review of the latest reported molecular mechanisms of cisplatin-induced ototoxicity, from extracellular to intracellular. We build up a signaling network starting with cisplatin entering into the inner ear through the blood labyrinth barrier, disrupting cochlear endolymph homeostasis, and activating inflammatory responses of the outer hair cells. After entering the hair cells, cisplatin causes hair cell death via DNA damage, redox system imbalance, and mitochondrial and endoplasmic reticulum dysfunction, culminating in programmed cell death including apoptosis, necroptosis, autophagic death, pyroptosis, and ferroptosis. Based on the mentioned mechanisms, prominent therapeutic targets, such as channel-blocking drugs...