Dual targeting agent Thiotert inhibits the progression of glioblastoma by inducing ER stress-dependent autophagy

Jianhong Dong; Yiming Qian; Wei Zhang; Qian Wang; Mengxian Jia; Juanqing Yue; Ziwei Fan; Yuanyuan Jiang; Lipei Wang; Yongjie Wang; Zhihui Huang; Lushan Yu; Ying Wang

doi:10.1016/j.biopha.2023.115867

Dual targeting agent Thiotert inhibits the progression of glioblastoma by inducing ER stress-dependent autophagy

Biomed Pharmacother. 2024 Jan:170:115867. doi: 10.1016/j.biopha.2023.115867. Epub 2023 Dec 15.

Authors

Jianhong Dong¹, Yiming Qian², Wei Zhang², Qian Wang², Mengxian Jia³, Juanqing Yue⁴, Ziwei Fan³, Yuanyuan Jiang², Lipei Wang², Yongjie Wang², Zhihui Huang⁵, Lushan Yu⁶, Ying Wang⁷

Affiliations

¹ Department of Clinical Research Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310053, Zhejiang, China; School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, Zhejiang, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, Zhejiang, China.
² School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, Zhejiang, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, Zhejiang, China.
³ Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
⁴ Department of Clinical Research Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310053, Zhejiang, China.
⁵ School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, Zhejiang, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, Zhejiang, China. Electronic address: huang0069@hznu.edu.cn.
⁶ Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou 310024, Zhejiang, China. Electronic address: yuls@zju.edu.cn.
⁷ Department of Clinical Research Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310053, Zhejiang, China. Electronic address: nancywangying@163.com.

PMID: 38101281
DOI: 10.1016/j.biopha.2023.115867

Abstract

Glioblastoma (GBM) is the most aggressive and lethal type of tumor in the central nervous system, characterized by a high incidence and poor prognosis. Thiotert, as a novel dual targeting agent, has potential inhibitory effects on various tumors. Here, we found that Thiotert effectively inhibited the proliferation of GBM cells by inducing G2/M cell cycle arrest and suppressed the migratory ability in vitro. Furthermore, Thiotert disrupted the thioredoxin (Trx) system while causing cellular DNA damage, which in turn caused endoplasmic reticulum (ER) stress-dependent autophagy. Knockdown of ER stress-related protein ATF4 in U251 cells inhibited ER stress-dependent autophagy caused by Thiotert to some extent. Orthotopic transplantation experiments further showed that Thiotert had the same anti-GBM activity and mechanism as in vitro. Conclusively, these results suggest that Thiotert induces ER stress-dependent autophagy in GBM cells by disrupting redox homeostasis and causing DNA damage, which provides new insight for the treatment of GBM.

Keywords: Autophagy; DNA damage; ER stress; GBM; Thiotert; Trx system.

MeSH terms

Apoptosis
Autophagy
Brain Neoplasms* / genetics
Cell Line, Tumor
Endoplasmic Reticulum Stress
G2 Phase Cell Cycle Checkpoints
Glioblastoma* / metabolism
Humans