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Identification of a co-target for enhancing efficacy of sorafenib in HCC through a quantitative modeling approach

Madhulika Mishra1, Priyanka Jayal1, Anjali A Karande1

  • 1Department of Biochemistry, Indian Institute of Science, Bengaluru, India.

The FEBS Journal
|August 24, 2018
PubMed

Insights

Sorafenib shows limited efficacy for liver cancer (HCC). Targeting glutathione S-transferase (GST) with ethacrynic acid synergistically enhances Sorafenib

Area of Science:

  • Biochemistry and Molecular Biology
  • Computational Biology
  • Cancer Research

Background:

  • Sorafenib is the sole approved drug for hepatocellular carcinoma (HCC) but exhibits limited efficacy, contributing to high mortality rates.
  • Sorafenib's known modulation of cancer cell redox homeostasis necessitates a quantitative understanding of its effects on redox status.

Purpose of the Study:

  • To develop a comprehensive kinetic model of the glutathione reaction network (GSHnet) incorporating Sorafenib-induced redox stress.
  • To investigate the impact of Sorafenib on redox dynamics in HCC of various etiologies and identify key regulatory enzymes.

Main Methods:

  • Developed a four-module kinetic model of the glutathione reaction network (GSHnet) to simulate Sorafenib effects.
  • Compared GSHnet simulations between healthy liver and HCC of six etiologies, and analyzed SFB treatment effects.
  • Employed metabolic control analysis to identify enzymes with significant control over the network and assessed synergistic effects ex vivo.

Main Results:

  • The model accurately differentiated redox profiles between healthy liver and HCC across six etiologies.
  • Sorafenib treatment induced differential hydrogen peroxide (H2O2) dynamics in all simulated conditions.
  • Glutathione S-transferase (GST) was identified as a key enzyme, showing the highest selective control coefficient.

Conclusions:

  • Glutathione S-transferase (GST) is a promising co-target for potentiating Sorafenib efficacy in HCC across diverse etiologies.
  • Ethacrynic acid (EA), a GST inhibitor, synergistically enhances Sorafenib's cytotoxic effect on HCC cells ex vivo.
  • Ethacrynic acid (EA) represents a potential candidate for repurposing in combination therapy with Sorafenib for HCC treatment.
Keywords:
co-targetglutathione metabolismliver cancermathematical modelingoxidative stressredox regulation

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