Experimental Study Of Metformin Againsts Cisplatin-induced Ototoxicity

BackgroundCisplatin is an anti-tumor drug which is widely used for the treatment of various solid tumors.Unfortunately,serious side-effected have affected the life of patients,such as hearing loss.Up to now,there are no preventive or therapeutic measures to the cisplatin-induced ototoxicity in the clinical use of cisplatin.PurposeThe study explored that the role of autophagy in cisplatin-induced ototoxicity,and the effect of metformin on cisplatin ototoxicity in cell,zebrafish,and mice.Furthermore,the molecular mechanism of metformin affecting the ototoxicity of cisplatin was examined.MethodsCell survival in HEI-OC1 cells was detected by CCK-8 assay.Fluorescence immunostaining was used to assess the level of autophagy.Western blot was used to detect the expression of LC3,p62,adenosine monophosphate-activated protein kinase(AMPK)、p-AMPK and transcription factor forkhead box protein O3(FOXO3a).Silencing AMPK was used to regulate the expression of AMPK in cells to detect the effect of metformin on the ototoxicity of cisplatin.Zebrafish hair cells were counted by a fluorescence microscope.Auditory brainstem response(ABR)was used to detect auditory threshold and cochlear hair cell count in C57BL/6 mice.ResultsIn this study,we showed that cisplatin induced activation of autophagy in the auditory cell HEI-OC1.Metformin not only had antagonistic effects on cisplatin ototoxicity in cell models,but also in zebra-fish and mice models.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).ConclusionAutophagy was activated after cisplatin injury to hair cells,after which metformin could activate autophagy to reduce cisplatin induced cell damage,possibly through activation of AMPK/ FOXO3 a signaling pathway.