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 IC(50) of 6 microM, whilst GST M1-1 was inhibited by
quinidine and its diastereoisomer
quinine with IC(50)s of 12 microM and 17 microM, respectively. GST M3-3 was inhibited by
tetracycline only with an IC(50) of 47 microM. GST P1-1 was the most susceptible
enzyme to inhibition by
antimalarials with IC(50) values of 1, 2, 1, 4, and 13 microM for
pyrimethamine,
artemisinin,
quinidine,
quinine and
tetracycline, respectively. The IC(50) 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 IC(50) values of 18, 27, 45 and 70 microM, 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.