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Novel synthetic protective compound, KR‐22335, against cisplatin‐induced auditory cell death
Author(s) -
Shin Yoo Seob,
Song Suk Jin,
Kang SungUn,
Hwang Hye Sook,
Jung YoungSik,
Kim ChulHo
Publication year - 2014
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.2852
Subject(s) - ototoxicity , cisplatin , zebrafish , apoptosis , chemistry , hair cell , pharmacology , reactive oxygen species , programmed cell death , biology , medicine , biochemistry , inner ear , anatomy , chemotherapy , gene
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.