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

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.

Multi-Targeting Anticancer Activity of a New 4-Thiazolidinone Derivative with Anti-HER2 Antibodies in Human AGS Gastric Cancer Cells

“…FV-429 exerts a dual ability to induce apoptosis and autophagy blockage. It was examined in gastric cancers or T-cell malignancies [ 29 , 30 ]. In our research, we focused on relevant proteins involved in the autophagy process: Beclin-1, LC3A, LC3B, and ATG5.…”

Autophagy blockage and lysosomal dysfunction are involved in diallyl sulfide‐induced inhibition of malignant growth in hepatocellular carcinoma cells

“…The accumulation of autophagosome or autolysosome may be resulted from the failure at the fusion or degradation phase. 27,28 To address whether DAS impairs the autophagosome-lysosome fusion, we examined the co-localization of GFP-LC3B and LysoTracker red, a dye used to label and track acidic organelles in live cells, such as lysosomes. We found that most GFP-LC3B puncta were not co-localized with LysoTracker red in DAS-treated cells (Figure 4C), indicating that DAS influenced the fusion of autophagosomes and lysosomes.…”

Non-apoptotic cell death-based cancer therapy: Molecular mechanism, pharmacological modulators, and nanomedicine

“…Therefore, inducing LMP plays an important regulatory role in LDCD. At present, many LDCD inducers including phenothiazine, flavonoid FV-429, ciprofloxacin or norfloxacin mainly induce LDCD by causing lysosomal damage and LMP 232 , 233 , 234 . Among them, FV-429 can promote LDCD in T cell malignant tumor cells by inducing lysosomal damage and LMP, thereby inhibiting tumor progression 233 .…”

“…At present, many LDCD inducers including phenothiazine, flavonoid FV-429, ciprofloxacin or norfloxacin mainly induce LDCD by causing lysosomal damage and LMP 232 , 233 , 234 . Among them, FV-429 can promote LDCD in T cell malignant tumor cells by inducing lysosomal damage and LMP, thereby inhibiting tumor progression 233 . Ciprofloxacin (CPX) or Norfloxacin (NFX) can cause LMP and lysosome damage and activate Bax and Bak to cause mitochondrial membrane permeability (MMP) and lysosomal-dependent cell death 232 .…”