title: Novel synthetic protective compound, KR-22335, against cisplatin-induced auditory cell death.
abstract: Cisplatin [cis-diammine-dichloroplatinum (II)] is a widely used chemotherapeutic agent, and one of its most severe side effects is ototoxicity. In the course of developing a new protective agent against cisplatin-induced ototoxicity, we have been interested in a novel synthetic compound, 3-Amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione (KR-22335). We evaluated the effectiveness of KR-22335 as an otoprotective agent against cisplatin-induced toxicity. The otoprotective effect of KR-22335 against cisplatin was tested in vitro in cochlear organs of Corti-derived cell lines, HEI-OC1, and in vivo in a zebrafish (Danio rerio) model. Cisplatin-induced apoptosis, cell cycle arrest and an increase in intracellular reactive oxygen species (ROS) generation were demonstrated in HEI-OC1 cells. KR-22335 inhibited cisplatin-induced apoptosis and mitochondrial injury in HEI-OC1 cells. KR-22335 inhibited cisplatin-induced activation of JNK, p-38, caspase-3 and PARP in HEI-OC1 cells. Scanning and transmission electron micrographs showed that KR-22335 prevented cisplatin-induced destruction of kinocilium and stereocilia in zebrafish neuromasts. Tissue TUNEL of neuromasts in zebrafish demonstrated that KR-22335 blocked cisplatin-induced TUNEL positive hair cells in neuromasts. The results of this study suggest that KR-22335 may prevent ototoxicity caused by the administration of cisplatin through the inhibition of mitochondrial dysfunction and suppression of ROS generation. KR-22335 may be considered as a potential candidate for protective agents against cisplatin-induced ototoxicity.
authors.affiliation: Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Korea; Center for Cell Death Regulating Biodrug, School of Medicine, Ajou University, Suwon, Korea.
authors.forename: Yoo Seob
authors.initials: YS
authors.lastname: Shin
authors.forename: Suk Jin
authors.initials: SJ
authors.lastname: Song
authors.forename: Sungun
authors.initials: S
authors.lastname: Kang
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Hwang
authors.forename: Young-Sik
authors.initials: YS
authors.lastname: Jung
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000009:adverse effects*; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015027:Zebrafish
chemical_list: C000591011:3-amino-3-(4-fluorophenyl)-1H-quinoline-2,4-dione; D000970:Antineoplastic Agents; D020011:Protective Agents; D015363:Quinolones; D017382:Reactive Oxygen Species; D002945:Cisplatin
keywords: apoptosis; cisplatin; hearing preservation; ototoxicity; zebrafish