Inhibiting DNA methylation alleviates cisplatin-induced hearing loss by decreasing oxidative stress-induced mitochondria-dependent apoptosis via the LRP1-PI3K/AKT pathway.
10.1016/j.apsb.2021.11.002
- Author:
Yingzi HE
1
;
Zhiwei ZHENG
1
;
Chang LIU
1
;
Wen LI
1
;
Liping ZHAO
1
;
Guohui NIE
2
;
Huawei LI
1
Author Information
1. 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.
2. 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.
- Publication Type:Journal Article
- Keywords:
5-mC, 5-methylcytosine;
ABR, auditory brainstem response;
Apoptosis;
Cisplatin;
DNMT;
DNMT, DNA methyltransferase;
EdU, 5-ethynyl-2′-deoxyuridine;
HCs, hair cells;
Hair cell;
IHCs, inner hair cells;
LRP1, low-density lipoprotein receptor-related protein 1;
MMP, mitochondrial membrane potential;
Mitochondrial dysfunction;
OCRs, oxygen consumption rates;
OHCs, outer hair cells;
PI, propidium iodide;
RG108;
ROS;
ROS, reactive oxygen species;
SGNs, spiral ganglion neurons;
Spiral ganglion neurons;
TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling
- From:
Acta Pharmaceutica Sinica B
2022;12(3):1305-1321
- CountryChina
- Language:English
-
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.
