P-gp MODULATING EFFECT OF THE PENTACYCLIC TRITERPENOID BETULIN, ISOLATED FROM LIGARIA CUNEIFOLIA, IN MULTIDRUG RESISTANT LEUKEMIC CELLS.

LAIOLO JERÓNIMO; JORAY MARIANA BELÉN; CARPINELLA MARÍA CECILIA

Mar del Plata

Congreso; Reunion anual de sociedades de biociencia SAIC SAFE SAB SAP AACYTAL NANOMED-ar HCS; 2019

SAIC SAFE SAB SAP AACYTAL NANOMED-ar HCS

Multidrug resistant (MDR) constitutesnowadays one of the major obstacle in cancer therapy, being the efflux of drugsby P-glycoprotein (P-gp) a predominant factor. Plants are recognized as a rich sourceof metabolites with structural diversity being an invaluable starting point fordrug discovery. With the aim of finding promising compounds to modulate MDRphenotype mediated by P-gp, 120 native and naturalized plants collected in the hillsof Córdoba, Argentina, were screened on K562 human myelogenous leukemia cellline and its MDR counterpart Lucena 1. Ligariacuneifolia was one of the most active and thus it was subjected tobioguided isolation to separate the active principle responsible for itsactivity. This process yielded the triterpenoid betulin (1).Intracellular doxorubicin (DOX)accumulation was determined, at non-cytotoxic concentrations determined by MTT, usingflow cytometry. Fluorescenceintensity radio (FIR) was calculated as the ratio between the fluorescence intensity of each cell linetreated and the fluorescence intensity of its respectivesolvent control. The activitywas confirmed by the MTT reversal assay.Compound 1 increased the accumulation of DOX at a minimum effective concentration (MEC) of 1.56 µM (FIR1.09±0.04) and increasedDOX cytotoxicity by a factor of 3.83± 0.26 at 12.5 µM and 1.29±0.075 at 0.39 µM showing no differenceswith respect to the same concentrations of verapamil, used as positive control(p-value ≤ 0.05). Compound 1 showed no effect at the MEC on K562cells.This is the firstreport regarding compound 1 as aninhibitor of the efflux mediated by P-gp. Thistriterpenoid could arise as scaffold to obtain novel P-gp inhibitors to use in combinationwith anticancer drugs for the improvement of leukemia therapies.