Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma.

Abstract

Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients' survival gain is limited and varies over a wide range depending on pathogenetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCCs. In this study, we utilized a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene list functional enrichment analysis and gene set enrichment analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum stress network model, combined with in vitro experiments, showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low-PDI-expression group.

CONCLUSION:

These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness. (Hepatology 2017;66:855-868).

• Authors: Jae-Kyung Won, Su Jong Yu, Chae Young Hwang, Sung-Hwan Cho, Sang-Min Park, Kwangsoo Kim, Won-Mook Choi, Hyeki Cho, Eun Ju Cho, Jeong-Hoon Lee, Kyung Bun Lee, Yoon Jun Kim, Kyung-Suk Suh, Ja-June Jang, Chung Yong Kim, Jung-Hwan Yoon, Kwang-Hyun Cho
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 66 Issue 3 Pg. 855-868 (09 2017) ISSN: 1527-3350 [Electronic] United States
• PMID: 28439950 (Publication Type: Journal Article)
• Copyright: © 2017 by the American Association for the Study of Liver Diseases.

Chemical References

• Antineoplastic Agents
• Phenylurea Compounds
• RNA, Messenger
• Niacinamide
• Sorafenib
• Protein Disulfide-Isomerases

Topics

• Animals
• Antineoplastic Agents (administration & dosage)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, mortality, pathology)
• Cohort Studies
• Disease Models, Animal
• Female
• Humans
• Kaplan-Meier Estimate
• Liver Neoplasms (drug therapy, mortality, pathology)
• Mice
• Mice, Inbred BALB C
• Middle Aged
• Niacinamide (administration & dosage, analogs & derivatives)
• Phenylurea Compounds (administration & dosage)
• Proportional Hazards Models
• Protein Disulfide-Isomerases (drug effects, metabolism)
• RNA, Messenger (drug effects, metabolism)
• Random Allocation
• Sorafenib
• Statistics, Nonparametric
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays (methods)