Novel synthetic protective compound, KR-22335, against cisplatin-induced auditory cell death
Article first published online: 8 JAN 2013
Copyright © 2013 John Wiley & Sons, Ltd.
Journal of Applied Toxicology
Volume 34, Issue 2, pages 191–204, February 2014
How to Cite
Shin, Y. S., Song, S. J., Kang, S., Hwang, H. S., Jung, Y.-S. and Kim, C.-H. (2014), Novel synthetic protective compound, KR-22335, against cisplatin-induced auditory cell death. J. Appl. Toxicol., 34: 191–204. doi: 10.1002/jat.2852
- Issue published online: 17 DEC 2013
- Article first published online: 8 JAN 2013
- Manuscript Revised: 20 NOV 2012
- Manuscript Accepted: 20 NOV 2012
- Manuscript Received: 3 OCT 2012
- hearing preservation;
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.