title: 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.
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdansk, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Głowacka-Rogacka
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Arciemiuk
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kupiec
authors.forename: Maria M
authors.initials: MM
authors.lastname: Bontemps-Gracz
authors.forename: Edward
authors.initials: E
authors.lastname: Borowski
authors.forename: Jolanta
authors.initials: J
authors.lastname: Tarasiuk
mesh_terms: 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
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001555:Benzene Derivatives; D007166:Immunosuppressive Agents; D011799:Quinazolines; C022049:perimidine; D004317:Doxorubicin; C027260:pirarubicin