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Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
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Published on: October 10, 2020

Characterization of new potential anticancer drugs designed to overcome glutathione transferase mediated resistance

Katarina Johansson1, Mika Ito, Carolien M S Schophuizen

  • 1Institute of Environmental Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden.

Molecular Pharmaceutics
|August 20, 2011
PubMed

Insights

Novel strategies targeting microsomal glutathione transferase 1 (MGST1) and glutathione transferase pi (GSTP) overcome drug resistance in cancer. Combining cisplatin with inhibitors or using GST-releasable doxorubicin (DOX) derivatives enhances chemotherapy effectiveness in GST-overexpressing cells.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Drug resistance in cancer, particularly against cytostatic agents like cisplatin and doxorubicin (DOX), is a significant clinical challenge.
  • Microsomal glutathione transferase 1 (MGST1) and glutathione transferase pi (GSTP) are frequently overexpressed in tumors, contributing to this drug resistance.
  • Targeting these GST enzymes presents a promising avenue for improving chemotherapy efficacy.

Purpose of the Study:

  • To develop novel strategies to overcome MGST1 and GSTP-mediated resistance to anticancer drugs.
  • To investigate the efficacy of ethacraplatin, a synthetic conjugate of cisplatin and ethacrynic acid, in reversing cisplatin resistance.
  • To synthesize and evaluate GST-releasable doxorubicin (DOX) prodrugs for selective toxicity in GST-overexpressing cancer cells.

Main Methods:

  • Synthesis of ethacraplatin by combining cisplatin with the GST inhibitor ethacrynic acid.
  • Treatment of MGST1-overexpressing MCF7 cells with ethacraplatin to assess cisplatin resistance reversal.
  • Synthesis of two DOX derivatives, 2,4-dinitrobenzenesulfonyl doxorubicin (DNS-DOX) and 4-mononitrobenzenesulfonyl doxorubicin (MNS-DOX).
  • Evaluation of DNS-DOX and MNS-DOX as substrates for MGST1 and GSTP, and their cytotoxic effects on cancer cells with varying GST expression levels.

Main Results:

  • Ethacraplatin effectively reversed cisplatin resistance in MGST1-overexpressing MCF7 cells.
  • DNS-DOX and MNS-DOX were identified as substrates for MGST1 and GSTP, releasing DOX.
  • MNS-DOX exhibited greater cytotoxicity towards MGST1-overexpressing cells compared to control cells, suggesting selective toxicity based on prodrug reactivity.
  • DNS-DOX eliminated DOX resistance and significantly increased toxicity in GSTP-overexpressing V79 cells, as demonstrated by clonogenic assays.

Conclusions:

  • Targeting MGST1 and GSTP offers a viable strategy to overcome cytostatic drug resistance in cancer.
  • Ethacraplatin demonstrates potential in reversing cisplatin resistance mediated by MGST1.
  • GST-releasable DOX prodrugs, particularly MNS-DOX, can achieve selective toxicity against GST-overexpressing cancer cells by controlling drug release rates.
  • These findings highlight the potential for enhanced chemotherapy efficacy and targeted cancer treatment by modulating GST activity.

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