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: Y S Shin, S J Song, S U Kang, H S Hwang, J W Choi, B H Lee, Y-S Jung, C-H Kim
• Journal: Neuroscience (Neuroscience) Vol. 232 Pg. 1-12 (Mar 01 2013) ISSN: 1873-7544 [Electronic] United States
• PMID: 23246618 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• 3-amino-3-(4-fluorophenyl)-1H-quinoline-2,4-dione
• Neuroprotective Agents
• Quinolones
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• Tumor Suppressor Protein p53
• NADPH Oxidases
• Nox3 protein, rat
• Extracellular Signal-Regulated MAP Kinases
• Casp3 protein, mouse
• Caspase 3
• Cisplatin

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Caspase 3 (metabolism)
• Cell Line
• Cisplatin (toxicity)
• Evoked Potentials, Auditory, Brain Stem (drug effects, physiology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Hearing Loss (physiopathology, prevention & control)
• Membrane Potential, Mitochondrial (drug effects, physiology)
• Mice
• NADPH Oxidases (metabolism)
• Neuroprotective Agents (chemistry, pharmacology)
• Organ of Corti (drug effects, physiopathology)
• Quinolones (chemical synthesis, pharmacology)
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Zebrafish