Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance.
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.
Mukanganyama
Stanley
S
Department of Biochemistry, University of Zimbabwe, Harare, Zimbabwe.
Widersten
Mikael
M
Naik
Yogeshkumar S
YS
Mannervik
Bengt
B
Hasler
Julia A
JA
D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins; D002330:Carmustine / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004976:Ethacrynic Acid / Q000494:pharmacology; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry; D012717:Sesquiterpenes / Q000494:pharmacology; D013752:Tetracycline / Q000494:pharmacology
D000962:Antimalarials; D037621:Artemisinins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; D012717:Sesquiterpenes; C031327:artemisinin; D011803:Quinine; D005982:Glutathione Transferase; D013752:Tetracycline; D011802:Quinidine; D004976:Ethacrynic Acid; D002330:Carmustine