Lim Kang Hyeon, Park Saemi, Han Eunjung, Baek Hyun Woo, Hyun Kyungtae, Hong Sumin, Kim Hwee-Jin, Lee Yunkyoung, Rah Yoon Chan, Choi June
Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine, Ansan Hospital, Ansan 15355, Republic of Korea.
Zebrafish Translational Medical Research Center, Korea University, Ansan 15355, Republic of Korea.
Int J Mol Sci. 2024 Dec 13;25(24):13363. doi: 10.3390/ijms252413363.
While cisplatin is an effective anti-tumor treatment, it induces ototoxicity through mechanisms involving DNA damage, oxidative stress, and programmed cell death. Rho-associated coiled-coil-containing protein kinase (ROCK) is essential for numerous cellular processes, including apoptosis regulation. Studies have suggested that ROCK inhibitors could prevent apoptosis and promote regeneration. We aimed to investigate the protective effects of the ROCK inhibitor fasudil against cisplatin-induced ototoxicity in a zebrafish model. The zebrafish larvae were exposed to 1 mM cisplatin alone or 1 mM cisplatin co-administered with varying concentrations of fasudil for 4 h. The surviving hair cell counts, apoptosis, reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔΨm), caspase 3 activity, and autophagy activation were assessed. Rheotaxis behavior was also examined. Cisplatin reduced hair cell counts; increased apoptosis, ROS production, and ΔΨm loss; and activated caspase 3 and autophagy. Fasudil (100 and 500 µM) mitigated cisplatin-induced hair cell loss, reduced apoptosis, and inhibited caspase 3 and autophagy activation. Rheotaxis in zebrafish was preserved by the co-administration of fasudil with cisplatin. Cisplatin induces hair cell apoptosis in zebrafish, whereas fasudil is a promising protective agent against cisplatin-induced ototoxicity.
虽然顺铂是一种有效的抗肿瘤治疗药物，但它通过涉及DNA损伤、氧化应激和程序性细胞死亡的机制诱导耳毒性。Rho相关卷曲螺旋蛋白激酶（ROCK）对包括细胞凋亡调节在内的众多细胞过程至关重要。研究表明，ROCK抑制剂可以预防细胞凋亡并促进再生。我们旨在研究ROCK抑制剂法舒地尔在斑马鱼模型中对顺铂诱导的耳毒性的保护作用。将斑马鱼幼虫单独暴露于1 mM顺铂或与不同浓度的法舒地尔共同给予1 mM顺铂4小时。评估存活的毛细胞计数、细胞凋亡、活性氧（ROS）水平、线粒体膜电位（ΔΨm）、半胱天冬酶3活性和自噬激活情况。还检查了趋流行为。顺铂减少了毛细胞计数；增加了细胞凋亡、ROS产生和ΔΨm丧失；并激活了半胱天冬酶3和自噬。法舒地尔（100和500 μM）减轻了顺铂诱导的毛细胞损失，减少了细胞凋亡，并抑制了半胱天冬酶3和自噬激活。法舒地尔与顺铂共同给药可保留斑马鱼的趋流性。顺铂诱导斑马鱼毛细胞凋亡，而法舒地尔是一种有前景的抗顺铂诱导耳毒性的保护剂。
