Aucubin protects mouse cochlear hair cells from cisplatin-induced ototoxicity via activation of the PI3K/AKT/STAT3 pathway

Yumeng Jiang; Zhuangzhuang Li; Qiang Ma; Wenqi Dong; Qingxiu Yao; Dongzhen Yu

doi:10.1016/j.bcp.2023.115440

Aucubin protects mouse cochlear hair cells from cisplatin-induced ototoxicity via activation of the PI3K/AKT/STAT3 pathway

Biochem Pharmacol. 2023 Mar:209:115440. doi: 10.1016/j.bcp.2023.115440. Epub 2023 Jan 30.

Authors

Yumeng Jiang¹, Zhuangzhuang Li¹, Qiang Ma¹, Wenqi Dong¹, Qingxiu Yao², Dongzhen Yu³

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai 200233, China; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai 200233, China.
² Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China. Electronic address: drqxyao@126.com.
³ Department of Otolaryngology-Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai 200233, China; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai 200233, China. Electronic address: 7250012023@shsmu.edu.cn.

PMID: 36720354
DOI: 10.1016/j.bcp.2023.115440

Abstract

Cisplatin is commonly used to treat cancers and is associated with a significant risk of irreversible sensorineural hearing loss. However, no effective preventive strategies are available for cisplatin-induced HL. Therefore, significant efforts have been made to discover new drugs protecting cochlear hair cells from cisplatin-induced damage. We found that a new phytochemical, aucubin, attenuated cisplatin-induced apoptosis, the production of reactive oxygen species, and mitochondrial dysfunction in House Ear Institute Organ of Corti 1 cells and cochlear hair cells. Moreover, aucubin attenuated cisplatin-induced sensorineural hearing loss and hair cells loss in vivo. Furthermore, RNA sequencing analysis revealed that the otoprotective effects of aucubin were mainly mediated by increased STAT3 phosphorylation via the PI3K/AKT pathway. Inhibition of the STAT3 signaling pathway with the inhibitor S3I-201 or siRNA disrupted the protective effects of aucubin on cisplatin-induced apoptosis. In conclusion, we identified an otoprotective effect of aucubin. Therefore, aucubin could be used to prevent cisplatin-induced ototoxicity.

Keywords: Aucubin; Cisplatin; Ototoxicity; PI3K/AKT; p-STAT3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Apoptosis
Cisplatin / pharmacology
Cochlea / metabolism
Hair Cells, Auditory
Hearing Loss* / chemically induced
Hearing Loss* / drug therapy
Hearing Loss* / prevention & control
Hearing Loss, Sensorineural* / drug therapy
Hearing Loss, Sensorineural* / metabolism
Mice
Ototoxicity* / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Reactive Oxygen Species / metabolism

Substances

Cisplatin
Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases
aucubin
Reactive Oxygen Species
Antineoplastic Agents