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Identification of a co‐target for enhancing efficacy of sorafenib in HCC through a quantitative modeling approach
Author(s) -
Mishra Madhulika,
Jayal Priyanka,
Karande Anjali A.,
Chandra Nagasuma
Publication year - 2018
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14641
Subject(s) - sorafenib , hepatocellular carcinoma , glutathione , drug , pharmacology , cancer , chemistry , repurposing , cancer cell , cancer research , biology , biochemistry , medicine , enzyme , ecology
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 (GSH net ), consisting of four modules and includes SFB‐induced redox stress. We compared GSH net 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 H 2 O 2 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.