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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Autophagy / drug effects
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Flavonoids / pharmacology*
  • HEK293 Cells
  • Hematologic Neoplasms / drug therapy*
  • Hematologic Neoplasms / pathology
  • Humans
  • Jurkat Cells
  • Leukemia-Lymphoma, Adult T-Cell / drug therapy
  • Leukemia-Lymphoma, Adult T-Cell / pathology
  • Lymphoma, Large-Cell, Anaplastic / drug therapy
  • Lymphoma, Large-Cell, Anaplastic / pathology
  • Lysosomes / drug effects*
  • Lysosomes / metabolism
  • Membrane Fusion / drug effects

Substances

  • Antineoplastic Agents
  • FV-429 compound
  • Flavonoids