The activity of latent benzoperimidine esters to inhibit P-glycoprotein and multidrug resistance-associated protein 1 dependent efflux of pirarubicin from several lines of multidrug resistant tumor cells.

ABSTRACT

Multidrug resistance of tumor cells is associated with the presence of membrane proteins responsible for the cytostatics export. Recently, we have synthesized a new family of benzoperimidines causing the futile cycle of MDR pumps. In this study, biological data for benzoperimidine esters are presented for selected cell lines sensitive (HL-60, GLC4, K562), P-gp resistant (HL-60/VINC, K562/DX), MRP1 resistant (HL-60/DX) and MRP1/LRP resistant (GLC4/DX). Their ability to inhibit the efflux of anthracycline antitumor drug, pirarubicin and to restore its accumulation in MDR cells was studied using a spectrofluorometric method which allows to follow the uptake and efflux of fluorescent molecules by living cells. Benzoperimidine esters had high effectiveness in inhibiting pirarubicin efflux and in restoring its accumulation in resistant cells. In contrast, examined esters were less active in vitro in restoration of pirarubicin cytotoxicity towards resistant cells because an enzymatic cleavage of esters occurs in presence of serum esterases.