Journal
AUTOPHAGY
Volume 18, Issue 3, Pages 678-694Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2021.1988357
Keywords
Antitumor; autophagy; liver cancer; lysosome; mtor; PPT1
Categories
Ask authors/readers for more resources
The new autophagy inhibitor GNS561 shows high liver tropism and potent antitumor activity, particularly against hepatocellular carcinoma. Its mechanism of action involves lysosomal disruption and induction of cell death in tumor cells.
Hepatocellular carcinoma is the most frequent primary liver cancer. Macroautophagy/autophagy inhibitors have been extensively studied in cancer but, to date, none has reached efficacy in clinical trials. In this study, we demonstrated that GNS561, a new autophagy inhibitor, whose anticancer activity was previously linked to lysosomal cell death, displayed high liver tropism and potent antitumor activity against a panel of human cancer cell lines and in two hepatocellular carcinoma in vivo models. We showed that due to its lysosomotropic properties, GNS561 could reach and specifically inhibited its enzyme target, PPT1 (palmitoyl-protein thioesterase 1), resulting in lysosomal unbound Zn2+ accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered location of MTOR (mechanistic target of rapamycin kinase), lysosomal membrane permeabilization, caspase activation and cell death. Accordingly, GNS561, for which a global phase 1b clinical trial in liver cancers was just successfully achieved, represents a promising new drug candidate and a hopeful therapeutic strategy in cancer treatment.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available