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Novel synthetic protective compound, KR-22335, against cisplatin-induced auditory cell death

Authors

  • Yoo Seob Shin,

    1. Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Korea
    2. Center for Cell Death Regulating Biodrug, School of Medicine, Ajou University, Suwon, Korea
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  • Suk Jin Song,

    1. Bio-organic Science Division, Korea Research Institute of Chemical Technology, Daejeon, Korea
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  • SungUn Kang,

    1. Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Korea
    2. Center for Cell Death Regulating Biodrug, School of Medicine, Ajou University, Suwon, Korea
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  • Hye Sook Hwang,

    1. Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Korea
    2. Center for Cell Death Regulating Biodrug, School of Medicine, Ajou University, Suwon, Korea
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  • Young-Sik Jung,

    1. Bio-organic Science Division, Korea Research Institute of Chemical Technology, Daejeon, Korea
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  • Chul-Ho Kim

    Corresponding author
    1. Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Korea
    2. Center for Cell Death Regulating Biodrug, School of Medicine, Ajou University, Suwon, Korea
    • Correspondence to: Chul-Ho Kim, Department of Otolaryngology, Ajou University School of Medicine, 5 Wonchon-Dong, Yeongtong-Gu, Suwon, Korea, 442-749. E-mail: ostium@ajou.ac.kr

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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. Copyright © 2013 John Wiley & Sons, Ltd.

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