FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-1

Chem Biol Interact. 2013 Sep 5;205(1):53-62. doi: 10.1016/j.cbi.2013.06.003. Epub 2013 Jun 13.


Objective: Glutathione transferase P1-1 (GST P1-1) is often overexpressed in tumor cells and is regarded as a contributor to their drug resistance. Inhibitors of GST P1-1 are expected to counteract drug resistance and may therefore serve as adjuvants in the chemotherapy of cancer by increasing the efficacy of cytostatic drugs. Finding useful inhibitors among compounds used for other indications would be a shortcut to clinical applications and a search for GST P1-1 inhibitors among approved drugs and other compounds was therefore conducted.

Methods: We tested 1040 FDA-approved compounds as inhibitors of the catalytic activity of purified human GST P1-1 in vitro.

Results: We identified chlorophyllide, merbromine, hexachlorophene, and ethacrynic acid as the most effective GST P1-1 inhibitors with IC50 values in the low micromolar range. For comparison, these compounds were even more potent in the inhibition of human GST A3-3, an enzyme implicated in steroid hormone biosynthesis. In distinction from the other inhibitors, which showed conventional inhibition patterns, the competitive inhibitor ethacrynic acid elicited strong kinetic cooperativity in the glutathione saturation of GST P1-1. Apparently, ethacrynic acid serves as an allosteric inhibitor of the enzyme.

Conclusion and practical implications: In their own right, the compounds investigated are less potent than desired for adjuvants in cancer chemotherapy, but the structures of the most potent inhibitors could serve as leads for the synthesis of more efficient adjuvants.

Keywords: Adjuvant chemotherapeutics; Enzyme inhibition; Ethacrynic acid; FDA-approved drugs; Glutathione transferase P1-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Chlorophyllides / pharmacology
  • Drug Approval
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Ethacrynic Acid / pharmacology
  • Glutathione S-Transferase pi / antagonists & inhibitors*
  • Glutathione Transferase / antagonists & inhibitors
  • Hexachlorophene / pharmacology
  • Humans
  • Kinetics
  • Merbromin / pharmacology
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Recombinant Proteins / antagonists & inhibitors
  • United States
  • United States Food and Drug Administration


  • Antineoplastic Agents
  • Chlorophyllides
  • Enzyme Inhibitors
  • Recombinant Proteins
  • GSTP1 protein, human
  • Glutathione S-Transferase pi
  • Glutathione Transferase
  • glutathione S-transferase A3-3, human
  • Hexachlorophene
  • Merbromin
  • Ethacrynic Acid