Premium
Inhibition of glutathione S‐transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance
Author(s) -
Mukanganyama Stanley,
Widersten Mikael,
Naik Yogeshkumar S.,
Mannervik Bengt,
Hasler Julia A.
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10054
Subject(s) - quinidine , pharmacology , quinine , artemisinin , plasmodium falciparum , glutathione , context (archaeology) , chemistry , drug resistance , in vivo , multiple drug resistance , enzyme , biology , biochemistry , malaria , microbiology and biotechnology , immunology , paleontology
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 μM, whilst GST M1‐1 was inhibited by quinidine and its diastereoisomer quinine with IC 50 s of 12 μM and 17 μM, respectively. GST M3‐3 was inhibited by tetracycline only with an IC 50 of 47 μM. GST P1‐1 was the most susceptible enzyme to inhibition by antimalarials with IC 50 values of 1, 2, 1, 4, and 13 μM 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 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. © 2001 Wiley‐Liss, Inc.