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Article: Flavonoid dimers as bivalent modulators for pentamidine and sodium stiboglucanate resistance in Leishmania

TitleFlavonoid dimers as bivalent modulators for pentamidine and sodium stiboglucanate resistance in Leishmania
Authors
Issue Date2007
PublisherAmerican Society for Microbiology.
Citation
Antimicrobial Agents And Chemotherapy, 2007, v. 51 n. 3, p. 930-940 How to Cite?
AbstractDrug resistance by overexpression of ATP-binding cassette (ABC) transporters is an impediment in the treatment of leishmaniasis. Flavonoids are known to reverse multidrug resistance (MDR) in Leishmania and mammalian cancers by inhibiting ABC transporters. Here, we found that synthetic flavonoid dimers with three (compound 9c) or four (compound 9d) ethylene glycol units exhibited a significantly higher reversing activity than other shorter or longer ethylene glycol-ligated dimers, with ∼3-fold sensitization of pentamidine and sodium stibogluconate (SSG) resistance in Leishmania, respectively. This modulatory effect was dosage dependent and not observed in apigenin monomers with the linker, suggesting that the modulatory effect is due to its bivalent nature. The mechanism of reversal activity was due to increased intracellular accumulation of pentamidine and total antimony in Leishmania. Compared to other MDR modulators such as verapamil, reserpine, quinine, quinacrine, and quinidine, compounds 9c and 9d were the only agents that can reverse SSG resistance. In terms of reversing pentamidine resistance, 9c and 9d have activities comparable to those of reserpine and quinacrine. Modulators 9c and 9d exhibited reversal activity on pentamidine resistance among LeMDR1 -/-, LeMDR1 +/+, and LeMDR1-overexpressed mutants, suggesting that these modulators are specific to a non-LeMDR1 pentamidine transporter. The LeMDR1 copy number is inversely related to pentamidine resistance, suggesting that it might be involved in importing pentamidine into the mitochondria. In summary, bivalency could be a useful strategy for the development of more potent ABC transporter modulators and flavonoid dimers represent a promising reversal agent for overcoming pentamidine and SSG resistance in parasite Leishmania. Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Persistent Identifierhttp://hdl.handle.net/10722/69509
ISSN
2015 Impact Factor: 4.415
2015 SCImago Journal Rankings: 2.322
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorWong, ILKen_HK
dc.contributor.authorChan, KFen_HK
dc.contributor.authorBurkett, BAen_HK
dc.contributor.authorZhao, Yen_HK
dc.contributor.authorChai, Yen_HK
dc.contributor.authorSun, Hen_HK
dc.contributor.authorChan, THen_HK
dc.contributor.authorChow, LMCen_HK
dc.date.accessioned2010-09-06T06:14:19Z-
dc.date.available2010-09-06T06:14:19Z-
dc.date.issued2007en_HK
dc.identifier.citationAntimicrobial Agents And Chemotherapy, 2007, v. 51 n. 3, p. 930-940en_HK
dc.identifier.issn0066-4804en_HK
dc.identifier.urihttp://hdl.handle.net/10722/69509-
dc.description.abstractDrug resistance by overexpression of ATP-binding cassette (ABC) transporters is an impediment in the treatment of leishmaniasis. Flavonoids are known to reverse multidrug resistance (MDR) in Leishmania and mammalian cancers by inhibiting ABC transporters. Here, we found that synthetic flavonoid dimers with three (compound 9c) or four (compound 9d) ethylene glycol units exhibited a significantly higher reversing activity than other shorter or longer ethylene glycol-ligated dimers, with ∼3-fold sensitization of pentamidine and sodium stibogluconate (SSG) resistance in Leishmania, respectively. This modulatory effect was dosage dependent and not observed in apigenin monomers with the linker, suggesting that the modulatory effect is due to its bivalent nature. The mechanism of reversal activity was due to increased intracellular accumulation of pentamidine and total antimony in Leishmania. Compared to other MDR modulators such as verapamil, reserpine, quinine, quinacrine, and quinidine, compounds 9c and 9d were the only agents that can reverse SSG resistance. In terms of reversing pentamidine resistance, 9c and 9d have activities comparable to those of reserpine and quinacrine. Modulators 9c and 9d exhibited reversal activity on pentamidine resistance among LeMDR1 -/-, LeMDR1 +/+, and LeMDR1-overexpressed mutants, suggesting that these modulators are specific to a non-LeMDR1 pentamidine transporter. The LeMDR1 copy number is inversely related to pentamidine resistance, suggesting that it might be involved in importing pentamidine into the mitochondria. In summary, bivalency could be a useful strategy for the development of more potent ABC transporter modulators and flavonoid dimers represent a promising reversal agent for overcoming pentamidine and SSG resistance in parasite Leishmania. Copyright © 2007, American Society for Microbiology. All Rights Reserved.en_HK
dc.languageengen_HK
dc.publisherAmerican Society for Microbiology.en_HK
dc.relation.ispartofAntimicrobial Agents and Chemotherapyen_HK
dc.rightsAntimicrobial Agents and Chemotherapy. Copyright © American Society for Microbiology.en_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleFlavonoid dimers as bivalent modulators for pentamidine and sodium stiboglucanate resistance in Leishmaniaen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0066-4804&volume=51&spage=930&epage=940&date=2007&atitle=Flavonoid+Dimers+as+Bivalent+Modulators+for+Pentamidine+and+Sodium+Stiboglucanate+Resistance+in+Leishmaniaen_HK
dc.identifier.emailSun, H:hsun@hkucc.hku.hken_HK
dc.identifier.authoritySun, H=rp00777en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1128/AAC.00998-06en_HK
dc.identifier.pmid17194831-
dc.identifier.pmcidPMC1803137-
dc.identifier.scopuseid_2-s2.0-33847607921en_HK
dc.identifier.hkuros132932en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33847607921&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume51en_HK
dc.identifier.issue3en_HK
dc.identifier.spage930en_HK
dc.identifier.epage940en_HK
dc.identifier.isiWOS:000244665500019-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridWong, ILK=7102513945en_HK
dc.identifier.scopusauthoridChan, KF=16315233100en_HK
dc.identifier.scopusauthoridBurkett, BA=36802327300en_HK
dc.identifier.scopusauthoridZhao, Y=7406636675en_HK
dc.identifier.scopusauthoridChai, Y=36785415300en_HK
dc.identifier.scopusauthoridSun, H=7404827446en_HK
dc.identifier.scopusauthoridChan, TH=7402687847en_HK
dc.identifier.scopusauthoridChow, LMC=7202533071en_HK

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