Inhibition of Glutathione S-Transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance.
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Date
2001-08-06
Journal Title
Journal ISSN
Volume Title
Publisher
Wiley-Liss, Inc.
Abstract
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 Al-l activity was inhibited by artemisinin
with an IC,, of 6 pM, whilst GST MI-l was inhibited by
quinidine and its diastereoisomer quinine with IC5,s of I2 pM
and 17 pM, respectively. GST M3-3 was inhibited by tetracycline
only with an IC,, of 47 pM. GST PI-l was the most
susceptible enzyme to inhibition by antimalarials with IC,,
values of I, 2, 1, 4, and 13 pM for pyrimethamine, arteniislnin,
quinidine, quinine and tetracycline, respectively. The
IC,, 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 PI-l activity was inhibited
by tetracycline, quinine, pyrimethamine and quinidine
with IC,, values of 18, 27, 45 and 70 pM, 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.
Description
An approval letter from editors is attached to the article
Keywords
Glutathione S-transferase, Antimalarials, Inhibition, Drug resistance, Chemomodulator
Citation
Mukanganyama et al. (2002) Inhibition of Glutathione S-Transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Wiley-Liss, Inc.