Next Article in Journal
Efficacy of Recombinant Methioninase (rMETase) on Recalcitrant Cancer Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models: A Review
Previous Article in Journal
Exploring Cellular Stress Response and Chaperones
Article Menu
Issue 5 (May) cover image

Export Article

Open AccessArticle

Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis

Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Korea
Bk21 Plus Research Center for Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea
Department of Otolaryngology-Head and Neck Surgery, Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan 31151, Korea
Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan 31151, Korea
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2019, 8(5), 409;
Received: 19 March 2019 / Revised: 25 April 2019 / Accepted: 30 April 2019 / Published: 2 May 2019
PDF [1888 KB, uploaded 20 May 2019]


Cisplatin-induced early-onset ototoxicity is linked to hearing loss. The mechanism by which cisplatin causes ototoxicity remains unclear. The purpose of this study was to identify the involvement of receptor-interacting protein kinase (RIP)3-dependent necroptosis in cisplatin-induced ototoxicity in vitro and in vivo. Sprague–Dawley rats (SD, 8 week) were treated via intraperitoneal (i.p.) injection with cisplatin (16 mg/kg for 1 day), and their hearing thresholds were measured by the auditory brainstem response (ABR) method. Hematoxylin and eosin (H & E) staining, immunohistochemistry, and western blots were performed to determine the effect of cisplatin-induced ototoxicity on cochlear morphology. Inhibitor experiments with necrostatin 1 (Nec-1) and Z-VAD were also performed in HEI-OC1 cell line. H&E stains revealed that the necroptotic changes were increased in the organ of Corti (OC) and spiral ganglion neurons (SGNs). Moreover, immunohistochemistry and western blot analysis showed that cisplatin treatment increased the protein levels of RIP3 in both OCs and SGNs. The treatment of Nec-1, a selective RIP1 inhibitor, resulted in markedly suppression of cisplatin-induced cell death in HEI-OC1 cells, whereas Z-VAD treatment did not change the cisplatin-induced cell death. Our results suggest that RIP3-dependent necroptosis was substantial in cisplatin-induced ototoxicity; inner cochlear regions, the OCs, and SGNs were especially sensitive to necroptosis. View Full-Text
Keywords: necroptosis; cisplatin; ototoxicity; organ of Corti; spiral ganglion neuron necroptosis; cisplatin; ototoxicity; organ of Corti; spiral ganglion neuron

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material


Share & Cite This Article

MDPI and ACS Style

Choi, M.-J.; Kang, H.; Lee, Y.Y.; Choo, O.-S.; Jang, J.H.; Park, S.-H.; Moon, J.-S.; Choi, S.J.; Choung, Y.-H. Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis. Cells 2019, 8, 409.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Cells EISSN 2073-4409 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top