Necroptosis and Apoptosis Contribute to Cisplatin and Aminoglycoside Ototoxicity
| Autor: | Robert Reed, Jeong Hwan Choi, John R. Lukens, Sihan Li, Michael R. Freeman, Ting-Ting Du, Douglas S. Ruhl, George T. Hashisaki, Elizabeth L. Wagner, Jung-Bum Shin, Kitae Kim |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Programmed cell death Necrosis Necroptosis Antineoplastic Agents Apoptosis 03 medical and health sciences Mice 0302 clinical medicine Ototoxicity Hair Cells Auditory medicine Evoked Potentials Auditory Brain Stem Animals Protein kinase A Research Articles Cisplatin Mice Knockout Caspase 8 Cell Death business.industry General Neuroscience Aminoglycoside medicine.disease Anti-Bacterial Agents Mice Inbred C57BL 030104 developmental biology Aminoglycosides Ear Inner Receptor-Interacting Protein Serine-Threonine Kinases Cancer research Female medicine.symptom business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 39(15) |
| ISSN: | 1529-2401 |
| Popis: | 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 thatex vivo, only apoptosis contributes to cisplatin and aminoglycoside ototoxicity, whilein 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 STATEMENTThe 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. |
| Databáze: | OpenAIRE |
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