2. Academic Validation
  3. Nitrovin (difurazone), an antibacterial growth promoter, induces ROS-mediated paraptosis-like cell death by targeting thioredoxin reductase 1 (TrxR1)

Nitrovin (difurazone), an antibacterial growth promoter, induces ROS-mediated paraptosis-like cell death by targeting thioredoxin reductase 1 (TrxR1)

  • Biochem Pharmacol. 2023 Apr:210:115487. doi: 10.1016/j.bcp.2023.115487.
Lin Zhao 1,  Bingling Zhong 1,  Yanyan Zhu 1,  Haoyi Zheng 1,  Xumei Wang 1,  Ying Hou 1,  Jin-Jian Lu 1,  Nana Ai 2,  Xiuli Guo 3,  Wei Ge 2,  Yan-Yan Ma 4,  Xiuping Chen 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
  • 2 Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, University of Macau, Macao, China.
  • 3 Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
  • 4 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China.
  • 5 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China; Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macao, China; MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao, China. Electronic address: xpchen@um.edu.mo.
PMID: 36893814 DOI: 10.1016/j.bcp.2023.115487
Abstract

Glioblastoma multiforme (GBM) is one of the most lethal malignant tumors in the human brain, with only a few chemotherapeutic drugs available after surgery. Nitrovin (difurazone) is widely used as an Antibacterial growth promoter in livestock. Here, we reported that nitrovin might be a potential Anticancer lead. Nitrovin showed significant cytotoxicity to a panel of Cancer cell lines. Nitrovin induced cytoplasmic vacuolation, Reactive Oxygen Species (ROS) generation, MAPK activation, and Alix inhibition but had no effect on Caspase-3 cleavage and activity, suggesting Paraptosis activation. Nitrovin-induced cell death of GBM cells was significantly reversed by cycloheximide (CHX), N-acetyl-l-cysteine (NAC), glutathione (GSH), and thioredoxin reductase 1 (TrxR1) overexpression. Vitamins C and E, inhibitors of pan-caspase, MAPKs, and endoplasmic reticulum (ER) stress failed to do so. Nitrovin-triggered cytoplasmic vacuolation was reversed by CHX, NAC, GSH, and TrxR1 overexpression but not by Alix overexpression. Furthermore, nitrovin interacted with TrxR1 and significantly inhibited its activity. In addition, nitrovin showed a significant Anticancer effect in a zebrafish xenograft model, which was reversed by NAC. In conclusion, our results showed that nitrovin induced non-apoptotic and paraptosis-like cell death mediated by ROS through targeting TrxR1. Nitrovin might be a promising Anticancer lead for further development.

Keywords

Glioblastoma; Nitrovin; Paraptosis; ROS; TrxR1.

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