Related Experiment Video
Updated: Sep 13, 2025
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
A Novel Chemotherapy Combination to Enhance Proteotoxic Cell Death in Hepatocellular Carcinoma Experimental Models
Carlos Perez-Stable1,2,3,4,5, Alicia de Las Pozas1, Teresita Reiner1,3
1Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA.
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. Rencofilstat + ixazomib maintained higher expression of XBP1s and genetic models suggested that XBP1s was a pro-survival protein early and pro-death protein at later times. Simultaneously, decreased PERK expression prevented the block in protein synthesis via phospho-eIF2α and likely further amplified proteotoxic stress. Rencofilstat + ixazomib did not have effects on XBP1s or PERK in non-cancer cells. Further genetic experiments revealed the pro-survival roles for cyclophilin A and B in mediating rencofilstat + ixazomib-induced cell death. In the Hep3B xenograft model, rencofilstat + ixazomib significantly inhibited tumor volumes/weights without general toxicity. We conclude that rencofilstat + ixazomib amplified proteotoxic stress in hepatocellular carcinoma past a threshold pro-survival pathways could not tolerate, whereas non-cancer cells were less affected.
Insights
Rencofilstat combined with ixazomib enhances proteotoxic stress and cell death in hepatocellular carcinoma, sparing non-cancer cells. This combination effectively targets cancer cells by modulating unfolded protein response pathways.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Proteasome inhibitors are effective in multiple myeloma but not solid tumors like hepatocellular carcinoma (HCC).
- Targeting proteotoxic stress pathways offers a potential therapeutic strategy for HCC.
- Identifying combinations that enhance cancer cell death with reduced non-cancerous toxicity is crucial.
Purpose of the Study:
- To identify a combination therapy that enhances proteotoxic stress and apoptotic cell death in HCC.
- To investigate the effects of rencofilstat and ixazomib on unfolded protein response (UPR) pathways in HCC.
- To evaluate the differential toxicity of the combination therapy on cancer versus non-cancer cells.
Main Methods:
- Combination treatment of HCC cells and non-cancer cells with rencofilstat (pan-cyclophilin inhibitor) and ixazomib (proteasome inhibitor).
- Analysis of unfolded protein response (UPR) factors X-box binding protein 1 (XBP1s) and PKR-like endoplasmic reticulum kinase (PERK).
- Genetic manipulation to explore the roles of cyclophilins and UPR components in cell death.
- In vivo efficacy and toxicity assessment using Hep3B xenograft models.
Main Results:
- Rencofilstat plus ixazomib induced significant apoptotic cell death in HCC cells but not in non-cancer cells.
- The combination therapy modulated UPR by maintaining XBP1s expression (pro-survival early, pro-death late) and decreasing PERK, amplifying proteotoxic stress.
- Cyclophilins A and B were identified as mediators of rencofilstat + ixazomib-induced cell death.
- In vivo studies showed significant inhibition of HCC tumor growth with no general toxicity.
Conclusions:
- Rencofilstat and ixazomib combination therapy effectively amplifies proteotoxic stress in HCC beyond the cells' survival capacity.
- This combination demonstrates selective toxicity towards HCC cells, sparing non-cancerous cells.
- The findings support rencofilstat + ixazomib as a promising therapeutic strategy for hepatocellular carcinoma.
Related Concept Videos
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:27Tumor Immunotherapy
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...