RT Journal Article
SR Electronic
T1 Necroptosis and Apoptosis Contribute to Cisplatin and Aminoglycoside Ototoxicity
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2951
OP 2964
DO 10.1523/JNEUROSCI.1384-18.2019
VO 39
IS 15
A1 Douglas Ruhl
A1 Ting-Ting Du
A1 Elizabeth L. Wagner
A1 Jeong Hwan Choi
A1 Sihan Li
A1 Robert Reed
A1 Kitae Kim
A1 Michael Freeman
A1 George Hashisaki
A1 John R. Lukens
A1 Jung-Bum Shin
YR 2019
UL http://www.jneurosci.org/content/39/15/2951.abstract
AB Ototoxic side effects of cisplatin and aminoglycosides have been extensively studied, but no therapy is available to date. Sensory hair cells, upon exposure to cisplatin or aminoglycosides, undergo apoptotic and necrotic cell death. Blocking these cell death pathways has therapeutic potential in theory, but incomplete protection and lack of therapeutic targets in the case of necrosis, has hampered the development of clinically applicable drugs. Over the past decade, a novel form of necrosis, termed necroptosis, was established as an alternative cell death pathway. Necroptosis is distinguished from passive necrotic cell death, in that it follows a cellular program, involving the receptor-interacting protein kinase (RIPK) 1 and RIPK3. In this study, we used pharmacological and genetic interventions in the mouse to test the relative contributions of necroptosis and caspase-8-mediated apoptosis toward cisplatin and aminoglycoside ototoxicity. We find that ex vivo, only apoptosis contributes to cisplatin and aminoglycoside ototoxicity, while in vivo, necroptosis as well as apoptosis are involved in both sexes. Inhibition of necroptosis and apoptosis using pharmacological compounds is thus a viable strategy to ameliorate aminoglycoside and cisplatin ototoxicity.SIGNIFICANCE STATEMENT The clinical application of cisplatin and aminoglycosides is limited due to ototoxic side effects. Here, using pharmaceutical and genetic intervention, we present evidence that two types of programmed cell death, apoptosis and necroptosis, contribute to aminoglycoside and cisplatin ototoxicity. Key molecular factors mediating necroptosis are well characterized and druggable, presenting new avenues for pharmaceutical intervention.