2. Academic Validation
  3. The organic arsenical-derived thioredoxin and glutathione system inhibitor ACZ2 induces apoptosis and autophagy in gastric cancer via ROS-dependent ER stress

The organic arsenical-derived thioredoxin and glutathione system inhibitor ACZ2 induces apoptosis and autophagy in gastric cancer via ROS-dependent ER stress

  • Biochem Pharmacol. 2022 Dec 30;115404. doi: 10.1016/j.bcp.2022.115404.
Yi Li 1,  Wenyan She 2,  Tangxi Guo 1,  Tianhe Huang 1,  Yixin Liu 1,  Pan Liu 1,  Xiaoran Xu 1,  Xinyu Wang 1,  Miao Wang 1,  Chaochao Yu 3,  Yi Liu 4,  Yongchang Wei 5
Affiliations

Affiliations

  • 1 Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei Cancer Clinical Study Center & Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China.
  • 2 College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China.
  • 3 Department of Integrated Chinese and Western Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
  • 4 College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China. Electronic address: yiliuchem@whu.edu.cn.
  • 5 Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei Cancer Clinical Study Center & Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China. Electronic address: weiyongchang@whu.edu.cn.
PMID: 36592709 DOI: 10.1016/j.bcp.2022.115404
Abstract

Developing novel drugs for gastric Cancer (GC) is greatly needed, and a Reactive Oxygen Species (ROS)-modulating strategy has been demonstrated to be useful for Cancer treatment. However, no organic arsenical-derived ROS-modulating drug has been developed in GC. Here, we constructed ACZ2 and investigated its efficacy and potential mechanism for GC in vitro and in vivo. Our data showed that ACZ2 could inhibit GC proliferation and cause G2/M phase arrest. Moreover, ACZ2 induced ROS accumulation by depleting glutathione (GSH) and TrxR1, triggering a subsequent ER stress response by activating the PERK/EIF2/ATF4/CHOP signalling pathways, which is a crucial step for ACZ2-mediated Apoptosis and Autophagy. Vitally, ROS scavenger (NAC) and ER stress inhibitor (4PBA) reversed ACZ2/ROS/ER stress-mediated Apoptosis and Autophagy. Our in vivo results clearly demonstrated that ACZ2 suppressed tumour growth in a GC xenograft model. Collectively, our data indicated that ACZ2 is a potential agent against GC.

Keywords

ACZ2; Apoptosis; Autophagy; ER stress; Gastric cancer; TrxR1.

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