2. Academic Validation
  3. FV-429 induces autophagy blockage and lysosome-dependent cell death of T-cell malignancies via lysosomal dysregulation

FV-429 induces autophagy blockage and lysosome-dependent cell death of T-cell malignancies via lysosomal dysregulation

  • Cell Death Dis. 2021 Jan 13;12(1):80. doi: 10.1038/s41419-021-03394-4.
Po Hu 1,  Jubo Wang 2,  Yingjie Qing 1,  Hui Li 1,  Wenzhuo Sun 1,  Xiaoxuan Yu 1 3,  Hui Hui 1,  Qinglong Guo 4,  Jingyan Xu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 3 Department of Pharmacology, School of medicine & Holostic integrative medicine, Nanjing University of Chinese Medicine, Nanjing, 210046, China.
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China. [email protected].
  • 5 Department of Hematology, The Affiliated DrumTower Hospital of Nanjing University Medical School, Nanjing, 210008, China. [email protected].
PMID: 33441536 DOI: 10.1038/s41419-021-03394-4
Abstract

It is widely accepted that lysosomes are essential for cell homeostasis, and Autophagy plays an important role in tumor development. Here, we found FV-429, a synthetic flavonoid compound, inhibited Autophagy flux, promoted autophagosomes accumulation, and inhibited lysosomal degradation in T-cell malignancies. These effects were likely to be achieved by lysosomal dysregulation. The destructive effects of FV-429 on lysosomes resulted in blockage of lysosome-associated membrane fusion, lysosomal membrane permeabilization (LMP), and cathepsin-mediated caspase-independent cell death (CICD). Moreover, we initially investigated the effects of Autophagy inhibition by FV-429 on the therapeutic efficacy of chemotherapy and found that FV-429 sensitized Cancer cells to chemotherapy agents. Our findings suggest that FV-429 could be a potential novel Autophagy Inhibitor with notable antitumor efficacy as a single agent.

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