Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs
Identifieur interne : 002490 ( Main/Exploration ); précédent : 002489; suivant : 002491Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs
Auteurs : Marko Vezmar [Canada] ; Elias Georges [Canada]Source :
- Biochemical Pharmacology [ 0006-2952 ] ; 2000.
English descriptors
- KwdEn :
- Teeft :
- Biochem, Biochem biophys, Biochem pharmacol, Biol, Biol chem, Borst, Cell lines, Chloroquine, Clin oncol, Cole, Deeley, Direct binding, Direct interaction, Doxorubicin, Doxorubicin resistance, Drug transport, Glutathione, Iaaq, Ltc4, Modulation ratio, Mrp1, Multidrug, Multidrug protein, Multidrug resistance, Multidrug resistance protein, Other drugs, Overexpression, Oxidative stress, Pharmacol, Photoaffinity, Plasma membranes, Primaquine, Proc natl acad, Quinidine, Quinine, Quinoline, Quinoline drugs, Reversal, Several drugs, Topoisomerase, Tumor cell lines, Tumor cells, Vezmar.
Abstract
Abstract: The overexpression of P-glycoprotein (P-gp) and the multidrug resistance-associated protein (MRP) have been shown to confer broad drug resistance in tumor cells. We have demonstrated previously direct binding between MRP and a quinoline-based photoreactive drug (iodo-azido-amino quinoline, IAAQ) (Vezmar et al., Biochem Biophys Res Commun 241: 104–111, 1997). In this report, we show the reversal of multidrug resistance in two MRP-overexpressing cell lines, HL60/AR and H69/AR, with four quinoline-based drugs. Non-toxic concentrations (5–20 μM) of chloroquine, quinine, quinidine, and primaquine potentiated the toxicity of doxorubicin in a concentration-dependent manner. These quinoline-based drugs showed a 5- to 10-fold decrease in the ic50 of doxorubicin in H69/AR and HL60/AR cells. Primaquine was the most active, with modulation ratios of 10- and 5-fold versus 8- and 3-fold with MK-571 for H69/AR and HL60/AR, respectively. Moreover, using IAAQ, we showed that molar excesses of chloroquine, quinine, quinidine, and MK-571 inhibit the photoaffinity labeling of MRP. Primaquine and vinblastine showed lesser inhibition of MRP photoaffinity labeling by IAAQ. Taken together, the results of this study demonstrated the reversal of doxorubicin resistance with several quinoline-based drugs. Moreover, these drugs have been shown to reverse P-gp-mediated MDR and are clinically well tolerated.
Url:
DOI: 10.1016/S0006-2952(00)00270-7
Affiliations:
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We have demonstrated previously direct binding between MRP and a quinoline-based photoreactive drug (iodo-azido-amino quinoline, IAAQ) (Vezmar et al., Biochem Biophys Res Commun 241: 104–111, 1997). In this report, we show the reversal of multidrug resistance in two MRP-overexpressing cell lines, HL60/AR and H69/AR, with four quinoline-based drugs. Non-toxic concentrations (5–20 μM) of chloroquine, quinine, quinidine, and primaquine potentiated the toxicity of doxorubicin in a concentration-dependent manner. These quinoline-based drugs showed a 5- to 10-fold decrease in the ic50 of doxorubicin in H69/AR and HL60/AR cells. Primaquine was the most active, with modulation ratios of 10- and 5-fold versus 8- and 3-fold with MK-571 for H69/AR and HL60/AR, respectively. Moreover, using IAAQ, we showed that molar excesses of chloroquine, quinine, quinidine, and MK-571 inhibit the photoaffinity labeling of MRP. Primaquine and vinblastine showed lesser inhibition of MRP photoaffinity labeling by IAAQ. Taken together, the results of this study demonstrated the reversal of doxorubicin resistance with several quinoline-based drugs. Moreover, these drugs have been shown to reverse P-gp-mediated MDR and are clinically well tolerated.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Québec</li></region><settlement><li>Montréal</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="Canada"><region name="Québec"><name sortKey="Vezmar, Marko" sort="Vezmar, Marko" uniqKey="Vezmar M" first="Marko" last="Vezmar">Marko Vezmar</name></region><name sortKey="Georges, Elias" sort="Georges, Elias" uniqKey="Georges E" first="Elias" last="Georges">Elias Georges</name><name sortKey="Georges, Elias" sort="Georges, Elias" uniqKey="Georges E" first="Elias" last="Georges">Elias Georges</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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