Original articles
Yingzi He, Zhiwei Zheng, Chang Liu, Wen Li, Liping Zhao, Guohui Nie, Huawei Li. Inhibiting DNA methylation alleviates cisplatin-induced hearing loss by decreasing oxidative stress-induced mitochondria-dependent apoptosis via the LRP1-PI3K/AKT pathway[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1305-1321

Inhibiting DNA methylation alleviates cisplatin-induced hearing loss by decreasing oxidative stress-induced mitochondria-dependent apoptosis via the LRP1-PI3K/AKT pathway
Yingzi Hea,b, Zhiwei Zhenga,b, Chang Liua,b, Wen Lia,b, Liping Zhaoa,b, Guohui Niee, Huawei Lia,b,c,d
a. ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China;
b. NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai 200031, China;
c. Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
d. The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China;
e. Department of Otolaryngology and Institute of Translational Medicine, Shenzhen Second People's Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen 518035, China
Abstract:
Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing loss. This study aimed to assess the potential effect of the DNA methyltransferase (DNMT) inhibitor RG108 on cisplatin-induced ototoxicity. Immunohistochemistry, apoptosis assay, and auditory brainstem response (ABR) were employed to determine the impacts of RG108 on cisplatin-induced injury in murine hair cells (HCs) and spiral ganglion neurons (SGNs). Rhodamine 123 and TMRM were utilized for mitochondrial membrane potential (MMP) assessment. Reactive oxygen species (ROS) amounts were evaluated by Cellrox green and Mitosox-red probes. Mitochondrial respiratory function evaluation was performed by determining oxygen consumption rates (OCRs). The results showed that RG108 can markedly reduce cisplatin induced damage in HCs and SGNs, and alleviate apoptotic rate by protecting mitochondrial function through preventing ROS accumulation. Furthermore, RG108 upregulated BCL-2 and downregulated APAF1, BAX, and BAD in HEI-OC1 cells, and triggered the PI3K/AKT pathway. Decreased expression of low-density lipoprotein receptor-related protein 1 (LRP1) and high methylation of the LRP1 promoter were observed after cisplatin treatment. RG108 treatment can increase LRP1 expression and decrease LRP1 promoter methylation. In conclusion, RG108 might represent a new potential agent for preventing hearing loss induced by cisplatin via activating the LRP1-PI3K/AKT pathway.
Key words:    Cisplatin    DNMT    Apoptosis    Hair cell    Spiral ganglion neurons    RG108    Mitochondrial dysfunction    ROS   
Received: 2021-06-03     Revised: 2021-10-29
DOI: 10.1016/j.apsb.2021.11.002
Funds: The authors would like to thank Yalin Huang for help with the confocal microscope. This work was supported by grants from the National Key R&D Program of China (No. 2017YFA0103900), the National Natural Science Foundation of China (Nos. 82071045, 81870728, 81830029, and 81970875), and Shanghai Rising-Star Program (19QA1401800).
Corresponding author: Guohui Nie,E-mai:nieguohui@email.szu.edu.cn;Huawei Li,E-mai:hwli@shmu.edu.cn     Email:nieguohui@email.szu.edu.cn;hwli@shmu.edu.cn
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Yingzi He
Zhiwei Zheng
Chang Liu
Wen Li
Liping Zhao
Guohui Nie
Huawei Li

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