title: A novel synthetic compound, 3-amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione, inhibits cisplatin-induced hearing loss by the suppression of reactive oxygen species: in vitro and in vivo study.
abstract: Cisplatin, a chemotherapeutic agent for treating various solid tumors, produces hearing loss in approximately half a million cancer patients annually in the United States. 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-22332). The effect of KR-22332 on cisplatin-induced cytotoxicity was analyzed in vitro in an organ of Corti-derived cell line (HEI-OC1), and in vivo in a zebrafish and rat model. Cisplatin-induced apoptosis, reactive oxygen species (ROS) generation and altered mitochondrial membrane potential (MMP) in HEI-OC1 cells were observed. KR-22332 significantly inhibited cisplatin-induced apoptosis, change of MMP, and intracellular ROS generation. KR-22332 markedly attenuated the cisplatin-induced loss and changes of auditory neuromasts in the zebrafish. Transtympanic administration of KR-22332 in a rat model was protective against cisplatin-induced hearing loss, as determined by click-evoked auditory brainstem response (p<0.01). Tissue terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling of rat cochlea demonstrated that KR-22332 blocked cisplatin-induced apoptosis. In addition, transtympanic administration of KR-22332 inhibited cisplatin-induced nicotinamide adenine dinucleotide phosphate-oxidase 3 (NOX3) overexpression in the rat cochlea. KR-22332 significantly reduced the expression of p-53, mitogen-activated protein kinases, caspase 3, and tumor necrosis factor-α compared to their significant increase after cisplatin treatment. The results of this study suggest that KR-22332 may prevent ototoxicity caused by the administration of cisplatin through the inhibition of mitochondrial dysfunction and the suppression of ROS generation. These novel findings implicate KR-22332 as a potential candidate for protective agent against cisplatin-induced ototoxicity.
authors.affiliation: Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea; Center for Cell Death Regulating Biodrug, School of Medicine, Ajou University, Suwon, Republic of Korea.
authors.forename: Y S
authors.initials: YS
authors.lastname: Shin
authors.affiliation: Bio-organic Science Division, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, Republic of Korea.
authors.forename: S J
authors.initials: SJ
authors.lastname: Song
authors.affiliation: Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea; Center for Cell Death Regulating Biodrug, School of Medicine, Ajou University, Suwon, Republic of Korea.
authors.forename: S U
authors.initials: SU
authors.lastname: Kang
authors.affiliation: Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea; Center for Cell Death Regulating Biodrug, School of Medicine, Ajou University, Suwon, Republic of Korea.
authors.forename: H S
authors.initials: HS
authors.lastname: Hwang
authors.affiliation: Department of Molecular Science & Technology, School of Medicine, Ajou University, Suwon, Republic of Korea.
authors.forename: J W
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea; Center for Cell Death Regulating Biodrug, School of Medicine, Ajou University, Suwon, Republic of Korea.
authors.forename: B H
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Bio-organic Science Division, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, Republic of Korea.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Jung
authors.affiliation: Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea; Center for Cell Death Regulating Biodrug, School of Medicine, Ajou University, Suwon, Republic of Korea. Electronic address: ostium@ajou.ac.kr.
authors.forename: C-H
authors.initials: CH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D034381:Hearing Loss / Q000503:physiopathology / Q000517:prevention & control*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009925:Organ of Corti / Q000187:drug effects / Q000503:physiopathology; D015363:Quinolones / Q000138:chemical synthesis / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015027:Zebrafish
chemical_list: C000591011:3-amino-3-(4-fluorophenyl)-1H-quinoline-2,4-dione; D018696:Neuroprotective Agents; D015363:Quinolones; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D019255:NADPH Oxidases; C534192:Nox3 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D002945:Cisplatin