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dc.contributor.author González, María Laura
dc.contributor.author Vera, Domingo Mariano Adolfo
dc.contributor.author Laiolo, Jerónimo
dc.contributor.author Joray, Mariana Belén
dc.contributor.author Maccioni, Mariana
dc.contributor.author Palacios, Sara Maria
dc.contributor.author Molina, Gabriela
dc.contributor.author Lanza Castronuovo, Priscila Ailin
dc.contributor.author Gancedo, Samanta
dc.contributor.author Rumjanek, Vivian
dc.contributor.author Carpinella, Maria Cecilia
dc.date.available 2017-11-30T22:08:06Z
dc.date.issued 2017-04
dc.identifier.citation González, María Laura; Vera, Domingo Mariano Adolfo; Laiolo, Jerónimo; Joray, Mariana Belén; Maccioni, Mariana; et al.; Mechanism Underlying the Reversal of Drug Resistance in P-Glycoprotein-Expressing Leukemia Cells by Pinoresinol and the Study of a Derivative; Frontiers; Frontiers in Pharmacology; 8; 4-2017; 1-19; 205
dc.identifier.uri http://hdl.handle.net/11336/29412
dc.description.abstract P-glycoprotein (P-gp) is a membrane protein associated with multidrug resistance (MDR) due to its key role in mediating the traffic of chemotherapeutic drugs outside cancer cells, leading to a cellular response that hinders efforts toward successful therapy. With the aim of finding agents that circumvent the MDR phenotype mediated by P-gp, 15 compounds isolated from native and naturalized plants of Argentina were screened. Among these, the non-cytotoxic lignan (±) pinoresinol successfully restored sensitivity to doxorubicin from 7 μM in the P-gp overexpressed human myelogenous leukemia cells, Lucena 1. This resistance-reversing effect was confirmed by competitively increasing the intracellular doxorubicin accumulation and by significantly inhibiting the efflux of doxorubicin and, to a lesser extent, that of rhodamine 123. The activity obtained was similar to that observed with verapamil. No such results were observed in the sensitive parental K562 cell line. To gain deeper insight into the mode of action of pinoresinol, its effect on P-gp function and expression was examined. The docking simulations indicated that the lignan bound to P-gp at the apex of the V-shaped transmembrane cavity, involving transmembrane helices 4, 5, and 6, and partially overlapped the binding region of tariquidar, which was used as a positive control. These results would shed some light on the nature of its interaction with P-gp at molecular level and merit further mechanistic and kinetic studies. In addition, it showed a maximum 29% activation of ATP hydrolysis and antagonized verapamil-stimulated ATPase activity with an IC50 of 20.9 μM. On the other hand, pinoresinol decreased the presence of P-gp in the cell surface. Derivatives of pinoresinol with improved activity were identified by docking studies. The most promising one, the non-cytotoxic 1-acetoxypinoresinol, caused a reversion of doxorubicin resistance from 0.11 μM and thus higher activity than the lead compound. It also caused a significant increase in doxorubicin accumulation. Results were similar to those observed with verapamil. The results obtained positioned these compounds as potential candidates for effective agents to overcome P-gp-mediated MDR, leading to better outcomes for leukemia chemotherapy.
dc.format application/pdf
dc.language.iso eng
dc.publisher Frontiers
dc.rights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject (±) PINORESINOL
dc.subject 1-ACETOXY-(+)-PINORESINOL
dc.subject MULTIDRUG RESISTANCE REVERSAL
dc.subject P-GLYCOPROTEIN
dc.subject PLANT-DERIVED COMPOUNDS
dc.subject.classification Bioquímica y Biología Molecular
dc.subject.classification Medicina Básica
dc.subject.classification CIENCIAS MÉDICAS Y DE LA SALUD
dc.title Mechanism Underlying the Reversal of Drug Resistance in P-Glycoprotein-Expressing Leukemia Cells by Pinoresinol and the Study of a Derivative
dc.type info:eu-repo/semantics/article
dc.type info:ar-repo/semantics/artículo
dc.type info:eu-repo/semantics/publishedVersion
dc.date.updated 2017-10-11T15:09:59Z
dc.identifier.eissn 1663-9812
dc.journal.volume 8
dc.journal.pagination 1-19; 205
dc.journal.pais Suiza
dc.description.fil Fil: González, María Laura. Universidad Católica de Córdoba; Argentina
dc.description.fil Fil: Vera, Domingo Mariano Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; Argentina
dc.description.fil Fil: Laiolo, Jerónimo. Universidad Católica de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil Fil: Joray, Mariana Belén. Universidad Católica de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil Fil: Maccioni, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
dc.description.fil Fil: Palacios, Sara Maria. Universidad Católica de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil Fil: Molina, Gabriela. Universidad Católica de Córdoba; Argentina
dc.description.fil Fil: Lanza Castronuovo, Priscila Ailin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; Argentina
dc.description.fil Fil: Gancedo, Samanta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
dc.description.fil Fil: Rumjanek, Vivian. Universidade Federal do Rio de Janeiro; Brasil
dc.description.fil Fil: Carpinella, Maria Cecilia. Universidad Católica de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.journal.title Frontiers in Pharmacology
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.3389/fphar.2017.00205
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fphar.2017.00205/full


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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)