A Novel Chemotherapy Combination to Enhance Proteotoxic Cell Death in Hepatocellular Carcinoma Experimental Models Without Killing Non-Cancer Cells.

ABSTRACT: Inhibitors of the ubiquitin-proteasome system increase proteotoxic stress and have achieved clinical success for multiple myeloma but not for solid cancers such as hepatocellular carcinoma. Our objective is to identify a combination with proteasome inhibitors that enhances proteotoxic stress and apoptotic cell death in hepatocellular carcinoma but with less toxicity to non-cancer cells. We found that rencofilstat, a pan-cyclophilin inhibitor, combined with ixazomib, a proteasome inhibitor, increased apoptotic cell death in hepatocellular carcinoma but not in umbilical vein or dermal fibroblast non-cancer cells. We then analyzed the effects of rencofilstat + ixazomib on XBP1s and PERK, critical factors in the unfolded protein response used by cells to survive proteotoxic stress. Rencofilsta

SUBMITTER: Perez-Stable C 

PROVIDER: S-EPMC12294793 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature