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Article: Reversal of P-glycoprotein-mediated multidrug resistance by a synthetic α-aminoxy peptidomimetic

TitleReversal of P-glycoprotein-mediated multidrug resistance by a synthetic α-aminoxy peptidomimetic
Authors
KeywordsLysine- peptidomimetic
Multidrug resistance reversal
P-glycoprotein inhibitor
Issue Date2012
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ijpharm
Citation
International Journal Of Pharmaceutics, 2012, v. 424 n. 1-2, p. 33-39 How to Cite?
AbstractThe lack of selectivity and adequate potency of currently known P-glycoprotein (P-gp) inhibitors obscured their further development for clinical use to circumvent P-gp-mediated multidrug resistance (MDR), which necessitates the investigation of novel ones with higher potency and better specificity. The present study investigated the reversal effect of a new synthetic α-aminoxy lysine-peptidomimetic (Lys-P) on P-gp-mediated MDR. Effects of Lys-P on cytotoxicity of P-gp substrate doxorubicin (Dox) and intracellular accumulation of another P-gp substrate rhodamine 123 were examined in HEK293 cells. Its interaction mechanism and effect on P-gp expression were further investigated using ATPase assay and Western blot in Caco-2 cells, respectively. Lys-P restored the cytotoxicity of Dox toward the resistant MDR1-transfected HEK293 and MCF-7 TX400 cells without affecting their corresponding parental cells. It also significantly increased intracellular accumulation (21-fold) of rhodamine 123 in HEK293 MDR1 cells. Further mechanistic studies demonstrated that in the Caco-2 cell monolayer model, Lys-P abolished the P-gp-mediated efflux of Dox due to uncompetitive inhibition of P-gp ATPase without altering P-gp expression. Our findings demonstrated that Lys-P can be used as a promising lead compound for further development into selective and efficient MDR reversing agents for combination use with P-gp substrate drugs in cancer chemotherapy. © 2012 Elsevier B.V. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/159318
ISSN
2023 Impact Factor: 5.3
2023 SCImago Journal Rankings: 0.954
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorMa, Ben_HK
dc.contributor.authorChai, Sen_HK
dc.contributor.authorLi, Nen_HK
dc.contributor.authorTo, KKWen_HK
dc.contributor.authorKan, WLTen_HK
dc.contributor.authorYang, Den_HK
dc.contributor.authorLin, Gen_HK
dc.date.accessioned2012-08-16T05:48:37Z-
dc.date.available2012-08-16T05:48:37Z-
dc.date.issued2012en_HK
dc.identifier.citationInternational Journal Of Pharmaceutics, 2012, v. 424 n. 1-2, p. 33-39en_HK
dc.identifier.issn0378-5173en_HK
dc.identifier.urihttp://hdl.handle.net/10722/159318-
dc.description.abstractThe lack of selectivity and adequate potency of currently known P-glycoprotein (P-gp) inhibitors obscured their further development for clinical use to circumvent P-gp-mediated multidrug resistance (MDR), which necessitates the investigation of novel ones with higher potency and better specificity. The present study investigated the reversal effect of a new synthetic α-aminoxy lysine-peptidomimetic (Lys-P) on P-gp-mediated MDR. Effects of Lys-P on cytotoxicity of P-gp substrate doxorubicin (Dox) and intracellular accumulation of another P-gp substrate rhodamine 123 were examined in HEK293 cells. Its interaction mechanism and effect on P-gp expression were further investigated using ATPase assay and Western blot in Caco-2 cells, respectively. Lys-P restored the cytotoxicity of Dox toward the resistant MDR1-transfected HEK293 and MCF-7 TX400 cells without affecting their corresponding parental cells. It also significantly increased intracellular accumulation (21-fold) of rhodamine 123 in HEK293 MDR1 cells. Further mechanistic studies demonstrated that in the Caco-2 cell monolayer model, Lys-P abolished the P-gp-mediated efflux of Dox due to uncompetitive inhibition of P-gp ATPase without altering P-gp expression. Our findings demonstrated that Lys-P can be used as a promising lead compound for further development into selective and efficient MDR reversing agents for combination use with P-gp substrate drugs in cancer chemotherapy. © 2012 Elsevier B.V. All rights reserved.en_HK
dc.languageengen_US
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ijpharmen_HK
dc.relation.ispartofInternational Journal of Pharmaceuticsen_HK
dc.subjectLysine- peptidomimetic-
dc.subjectMultidrug resistance reversal-
dc.subjectP-glycoprotein inhibitor-
dc.subject.meshAdenosine Triphosphatases - metabolismen_HK
dc.subject.meshAntibiotics, Antineoplastic - pharmacologyen_HK
dc.subject.meshCaco-2 Cellsen_HK
dc.subject.meshCell Line, Tumoren_HK
dc.subject.meshCell Survival - drug effectsen_HK
dc.subject.meshDoxorubicin - pharmacologyen_HK
dc.subject.meshDrug Resistance, Multiple - drug effectsen_HK
dc.subject.meshDrug Resistance, Neoplasm - drug effectsen_HK
dc.subject.meshFluorescent Dyes - pharmacologyen_HK
dc.subject.meshHEK293 Cellsen_HK
dc.subject.meshHumansen_HK
dc.subject.meshLysine - analogs & derivatives - pharmacologyen_HK
dc.subject.meshP-Glycoprotein - metabolismen_HK
dc.subject.meshPeptidomimetics - pharmacologyen_HK
dc.subject.meshRhodamine 123 - pharmacologyen_HK
dc.titleReversal of P-glycoprotein-mediated multidrug resistance by a synthetic α-aminoxy peptidomimeticen_HK
dc.typeArticleen_HK
dc.identifier.emailYang, D:yangdan@hku.hken_HK
dc.identifier.authorityYang, D=rp00825en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.ijpharm.2011.12.046en_HK
dc.identifier.pmid22226881-
dc.identifier.scopuseid_2-s2.0-84863396516en_HK
dc.identifier.hkuros203816en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84863396516&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume424en_HK
dc.identifier.issue1-2en_HK
dc.identifier.spage33en_HK
dc.identifier.epage39en_HK
dc.identifier.isiWOS:000301906300005-
dc.publisher.placeNetherlandsen_HK
dc.identifier.scopusauthoridMa, B=51864116400en_HK
dc.identifier.scopusauthoridChai, S=36336776300en_HK
dc.identifier.scopusauthoridLi, N=36065390000en_HK
dc.identifier.scopusauthoridTo, KKW=7101911923en_HK
dc.identifier.scopusauthoridKan, WLT=25823106300en_HK
dc.identifier.scopusauthoridYang, D=7404800756en_HK
dc.identifier.scopusauthoridLin, G=26643369300en_HK
dc.identifier.citeulike10204908-
dc.identifier.issnl0378-5173-

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