Identification of a co‐target for enhancing efficacy of sorafenib in HCC through a quantitative modeling approach. (6th September 2018)

• Record Type: Journal Article
• Authors: Mishra, Madhulika; Jayal, Priyanka; Karande, Anjali A.; Chandra, Nagasuma
• Is Part Of: FEBS journal. Volume 285:Number 21(2018)
• Page Start: 3977
• Page End: 3992
• Publication Date: 2018-09-06
• Subjects: co‐target -- glutathione metabolism -- liver cancer -- mathematical modeling -- oxidative stress -- redox regulation; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.14641
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : Sorafenib (SFB), a multi‐kinase inhibitor, is the only approved drug for treating hepatocellular carcinoma (HCC). However, SFB shows low efficacy in many cases. HCC related mortality therefore remains to be high worldwide. SFB, a multi‐kinase inhibitor is also known to modulate the redox homeostasis in cancer cells. To understand the effect of SFB on the redox status, a quantitative understanding of the system is necessary. Kinetic modeling of the relevant pathways is a useful approach for obtaining a quantitative understanding of the pathway dynamics and to rank the individual factors based on the extent of influence they wield on the pathway. Here, we report a comprehensive model of the glutathione reaction network (GSHnet ), consisting of four modules and includes SFB‐induced redox stress. We compared GSHnet simulations for HCC of six different etiologies with healthy liver, and correctly identified the expected variations in cancer. Next, we studied alterations induced in the system upon SFB treatment and observed differential H2 O2 dynamics in all the conditions. Using metabolic control analysis, we identified glutathione S ‐transferase (GST) as the enzyme with the highest selective control coefficient, making it an attractive co‐target for potentiating the action of SFB across all six etiologies. As a proof‐of‐concept, we selected ethacrynic acid (EA), a known inhibitor of GST, and verified ex vivo that EA synergistically potentiates the cytotoxic effect of SFB. Being an FDA approved drug, EA is a promising candidate for repurposing as a combination therapy with SFB for HCC treatment. Abstract : Sorafenib (SFB), a widely used drug for treating hepatocellular carcinoma (HCC), is metabolized by glutathione, producing H2 O2 in the process, adding significantly to its efficacy as an anticancer drug. Simulations using a kinetic model of the glutathione metabolism in HCC identified glutathione‐ S ‐transferase as a promising co‐target for potentiating the action of SFB. We demonstrate this with a proof‐of‐concept experimental validation.