title: Inhibition of human glutathione transferases by multidrug resistance chemomodulators in vitro.
abstract: Reversal of the drug-resistance phenotype in cancer cells usually involves the use of a chemomodulator that inhibits the function of a resistance-related protein. The aim of this study was to investigate the effects of MDR chemomodulators on human recombinant glutathione S-transferase (GSTs) activity. IC50 values for 15 MDR chemomodulators were determined using 1-chloro-dinitrobenzene (CDNB), cumene hydroproxide (CuOOH) and anticancer drugs as substrates. GSTs A1, P1 and M1 were inhibited by O6-benzylguanine (IC50s around 30 microM), GST P1-1 by sulphinpyrazone (IC50 = 66 microM), GST Al-1 by sulphasalazine, and camptothecin (34 and 74 microM respectively), and GST M1-1 by sulphasalazine, camptothecin and indomethacin (0.3, 29 and 30 microM respectively) using CDNB as a substrate. When ethacrynic acid (for GST P1-1), CuOOH (for A1-1) and 1,3-bis (2-chloroethyl)-1-nitrosourea (for GST M1-1) were used as substrates, these compounds did not significantly inhibit the GST isoforms. However, progesterone was a potent inhibitor of GST P1-1 (IC50 = 1.4 microM) with ethacrynic acid as substrate. These results suggest that the target of chemomodulators in vivo could be a specific resistance-related protein.
authors.affiliation: Biomolecular Interactions Analyses Group, Department of Biochemistry, University of Zimbabwe, Box MP 167, Mount Pleasant, Harare, Zimbabwe.
authors.forename: Rose
authors.initials: R
authors.lastname: Hayeshi
authors.forename: Farai
authors.initials: F
authors.lastname: Chinyanga
authors.forename: Shylet
authors.initials: S
authors.lastname: Chengedza
authors.forename: Stanley
authors.initials: S
authors.lastname: Mukanganyama
mesh_terms: D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015870:Gene Expression; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D005982:Glutathione Transferase