2. Academic Validation
  3. Pleiotropic effects of a mitochondrion-targeted glutathione reductase inhibitor on restraining tumor cells

Pleiotropic effects of a mitochondrion-targeted glutathione reductase inhibitor on restraining tumor cells

  • Eur J Med Chem. 2023 Feb 15:248:115069. doi: 10.1016/j.ejmech.2022.115069.
Renshuai Zhang 1,  Na Xiao 2,  Qi Xu 3,  Qiuyu Gong 4,  Fandong Kong 5,  Hongfei Jiang 6
Affiliations

Affiliations

  • 1 The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China; Cancer Institute, Qingdao University, Qingdao, 266071, China.
  • 2 State Key Laboratory of Crop Biology, College of Agronomy, Shandong Agriculture University, Tai'an, Shandong, 271018, China.
  • 3 School of Pharmaceutical Sciences, Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China.
  • 4 Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
  • 5 Key Laboratory of Chemistry and Engineering of Forest Products, State Ethnic Affairs Commission, Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products, School of Chemistry and Chemical Engineering, Guangxi Minzu University, Nanning, 530006, China. Electronic address: kongfandong0127@126.com.
  • 6 The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China; Cancer Institute, Qingdao University, Qingdao, 266071, China. Electronic address: jianghongfei@qdu.edu.cn.
PMID: 36610249 DOI: 10.1016/j.ejmech.2022.115069
Abstract

Mitochondria has been identified as a target for tumor therapy. Agents preferentially concentrated in mitochondria may exert more potent antitumor effects by interfering with the normal function of mitochondria. Glutathione reductase (GR) in mitochondria is a crucial antioxidant enzyme to maintain mitochondrial function, and has been recognized as an important target for the development of Anticancer drugs. Herein, we present a triphenylphosphonium-modified Anticancer agent, MT-1, which can preferentially accumulate in mitochondria and bind to GR by covalent binding manner. As a result, morphology and function of mitochondria were severely damaged, as well as cellular energy supply was severely impeded due to the simultaneously inhibition against mitochondrial respiration and glycolysis. Moreover, MT-1 was found to bind to a completely new site of GR (C278) that has never considered as binding site of inhibitors before. This new binding mode led to the change of GR structure, which affected the stability of the transition state of the catalytic process, and finally led to the inhibition of GR activity. Thus, current study provided a potentially novel tumor therapeutic strategy by targeting novel sites of GR in mitochondrion.

Keywords

Antitumor agents; Glutathione reductase; Metabolism; Mitochondria; Redox homeostasis.

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