A strategy to overcome multidrug resistance in cancer cells involves treatment with a combination of the antineoplastic agent and a chemomodulator that inhibits the activity of the resistance-causing protein. The aim of our study was to investigate the effects of antimalarial drugs on human recombinant glutathione S-transferase (GSTs) activity in the context of searching for effective and clinically acceptable inhibitors of these enzymes. Human recombinant GSTs heterologously expressed in Escherichia coli were used for inhibition studies. GST A1-1 activity was inhibited by artemisinin with an IC50 of 6 μM, whilst GST M1-1 was inhibited by quinidine and its diastereoisomer quinine with IC50s of 12 μM and 17 μM, respectively. GST M3-3 was inhibited by tetracycline only with an IC50 of 47 μM. GST P1-1 was the most susceptible enzyme to inhibition by antimalarials with IC50 values of 1, 2, 1, 4, and 13 μM for pyrimethamine, artemisinin, quinidine, quinine and tetracycline, respectively. The IC50 values obtained for artemisinin, quinine, quinidine and tetracycline are below peak plasma concentrations obtained during therapy of malaria with these drugs. It seems likely, therefore, that GSTs may be inhibited in vivo at doses normally used in clinical practice. Using the substrate ethacrynic acid, a diuretic drug also used as a modulator to overcome drug resistance in tumour cells, GST P1-1 activity was inhibited by tetracycline, quinine, pyrimethamine and quinidine with IC50 values of 18, 27, 45 and 70 μM, respectively. The ubiquitous expression of GSTs in different malignancies suggests that the addition of nontoxic reversing agents such as antimalarials could enhance the efficacy of a variety of alkylating agents. © 2002 Wiley-Liss, Inc.
