Mechanism Underlying the Reversal of Drug Resistance in P-Glycoprotein-Expressing Leukemia Cells by Pinoresinol and the Study of a Derivative

CARPINELLA, MARÍA C.; GONZÁLEZ, MARÍA L.; VERA, D. MARIANO A.; LAIOLO, JERÓNIMO; JORAY, MARIANA B.; MACCIONI, MARIANA; PALACIOS, SARA M.; MOLINA, GABRIELA; LANZA, PRISCILA A.; GANCEDO, SAMANTA; RUMJANEK, VIVIAN

Frontiers in Pharmacology

Frontiers

Año: 2017 vol. 8

-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