Inhibition of Glutathione S-Transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance.

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dc.contributor.authorMukanganyama, Stanley
dc.contributor.authorWidersten, Mikael
dc.contributor.authorNaik, Yogeshkumar S.
dc.contributor.authorMannervik, B.
dc.contributor.authorHasler, Julia A.
dc.date.accessioned2015-04-09T10:09:10Z
dc.date.accessioned2023-06-23T14:00:24Z
dc.date.available2015-04-09T10:09:10Z
dc.date.available2023-06-23T14:00:24Z
dc.date.issued2001-08-06
dc.descriptionAn approval letter from editors is attached to the articleen_US
dc.description.abstractA 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.en_US
dc.description.sponsorshipInternational Program in Chemical Sciences (IPICS), Uppsala University, Uppsala, Sweden; Research Board University of Zimbabwe, Harare Zimbabwe.en_US
dc.identifier.citationMukanganyama et al. (2002) Inhibition of Glutathione S-Transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Wiley-Liss, Inc.en_US
dc.identifier.otherD.O.I: 10.1002
dc.identifier.urihttp://196.220.97.103:4000/handle/123456789/484
dc.language.isoenen_US
dc.publisherWiley-Liss, Inc.en_US
dc.relation.ispartofseriesInternational Journal of Cancer;97,000-000
dc.rights.licenseThis article was downloaded from NUST Institutional repository, and is made available under the terms and conditions as set out in the Institutional Repository Policy.en_US
dc.subjectGlutathione S-transferaseen_US
dc.subjectAntimalarialsen_US
dc.subjectInhibitionen_US
dc.subjectDrug resistanceen_US
dc.subjectChemomodulatoren_US
dc.titleInhibition of Glutathione S-Transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance.en_US
dc.typeArticleen_US
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