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.
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.
Głowacka-Rogacka
Dorota
D
Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdansk, Poland.
Arciemiuk
Małgorzata
M
Kupiec
Agnieszka
A
Bontemps-Gracz
Maria M
MM
Borowski
Edward
E
Tarasiuk
Jolanta
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism / Q000493:pharmacokinetics*; D001555:Benzene Derivatives / Q000494:pharmacology*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D011799:Quinazolines; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001555:Benzene Derivatives; D007166:Immunosuppressive Agents; D011799:Quinazolines; C022049:perimidine; D004317:Doxorubicin; C027260:pirarubicin