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Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
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Glutathione S-conjugates as prodrugs to target drug-resistant tumors

Emma E Ramsay1, Pierre J Dilda1

  • 1Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales Sydney, NSW, Australia.

Frontiers in Pharmacology
|August 27, 2014
PubMed

Insights

Glutathione S-transferases (GST) and gamma-glutamyl transferases (γGT) are key enzymes in detoxifying foreign compounds. Targeting cancer cells using drugs activated by these enzymes shows promise for effective anticancer therapies.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Organisms are exposed to xenobiotics, necessitating detoxification pathways.
  • Glutathione S-transferases (GST) catalyze xenobiotic conjugation with glutathione (GSH).
  • Mercapturic acid pathway end products can be cytotoxic, involving GST and gamma-glutamyl transferases (γGT).

Purpose of the Study:

  • To explore the role of GST and γGT in cancer cell resistance and aggressiveness.
  • To investigate the potential of targeting tumors using drugs activated by GST or γGT.
  • To confirm the efficacy of glutathione S-conjugates as anticancer agents.

Main Methods:

  • Review of studies on GST and γGT expression in cancer.
  • Analysis of strategies employing GST- or γGT-activated prodrugs.
  • Examination of clinical success of specific anticancer drugs like TLK286, GSAO, and Darinaparsin.

Main Results:

  • Elevated GST and γGT expression correlates with aggressive and resistant cancer phenotypes.
  • Selective tumor targeting using enzyme-activated prodrugs is a viable strategy.
  • Recent successes with GST-activated (TLK286) and γGT-activated (GSAO, Darinaparsin) drugs validate this approach.

Conclusions:

  • GST and γGT are crucial in cancer cell resistance and can be exploited for targeted therapy.
  • GST- and γGT-activated prodrugs represent a promising class of anticancer drugs.
  • The mercapturic acid pathway enzymes offer significant therapeutic targets in oncology.
Keywords:
cancerdrug resistancegamma-glutamyl transferaseglutathione S-conjugateglutathione transferaseprodrug

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