PUBLICATION
Metformin Alleviates Cisplatin-Induced Ototoxicity by Autophagy Induction Possibly via the AMPK/FOXO3a Pathway
- Authors
- Liang, Z., Zhang, T., Zhan, T., Cheng, G., Zhang, W., Jia, H., Yang, H.
- ID
- ZDB-PUB-210225-4
- Date
- 2021
- Source
- Journal of neurophysiology 125(4): 1202-1212 (Journal)
- Registered Authors
- Keywords
- AMPK, FOXO3a, autophagy, cisplatin-ototoxicity, metformin
- MeSH Terms
-
- Animals
- Antineoplastic Agents/toxicity*
- Autophagy/drug effects*
- Cells, Cultured
- Cisplatin/toxicity*
- Disease Models, Animal
- Forkhead Box Protein O3/drug effects*
- Hair Cells, Auditory/drug effects*
- Male
- Metformin/administration & dosage
- Metformin/pharmacology*
- Mice
- Mice, Inbred C57BL
- Neuroprotective Agents/administration & dosage
- Neuroprotective Agents/pharmacology*
- Ototoxicity/drug therapy*
- Ototoxicity/etiology*
- Protein Kinases/drug effects*
- Zebrafish
- PubMed
- 33625942 Full text @ J. Neurophysiol.
Citation
Liang, Z., Zhang, T., Zhan, T., Cheng, G., Zhang, W., Jia, H., Yang, H. (2021) Metformin Alleviates Cisplatin-Induced Ototoxicity by Autophagy Induction Possibly via the AMPK/FOXO3a Pathway. Journal of neurophysiology. 125(4):1202-1212.
Abstract
Cisplatin is an anti-tumor drug which is widely used for treatment of various solid tumors. Unfortunately, patients are often troubled by serious side effects, especially hearing loss. Up to now, there have been no clear and effective measures to prevent cisplatin-induced ototoxicity in clinical use. We explored the role of autophagy and the efficacy of metformin in cisplatin-induced ototoxicity in cells, zebrafish, and mice. Furthermore, the underlying molecular mechanism of how metformin affects cisplatin-induced ototoxicity was examined. In in-vitro experiments, autophagy levels in HEI-OC1 cells were assessed using fluorescence and western blot analyses. In in-vivo experiments, whether metformin had a protective effect against cisplatin ototoxicity was validated in zebrafish and C57BL/6 mice. The results showed that cisplatin induced autophagy activation in HEI-OC1 cells. Metformin exerted antagonistic effects against cisplatin ototoxicity in HEI-OC1 cells, zebrafish and mice. Notably, metformin activated autophagy and increased the expression levels of the adenosine monophosphate-activated protein kinase (AMPK) and the transcription factor Forkhead box protein O3 (FOXO3a), while cells with AMPK silencing displayed otherwise. Our findings indicate that metformin alleviates cisplatin-induced ototoxicity possibly through AMPK/FOXO3a-mediated autophagy machinery. This study underpins further researches on the prevention and treatment of cisplatin ototoxicity.
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