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Crown ethers reverse P-glycoprotein-mediated multidrug resistance in cancer cells

Guberović, Iva; Marjanović, Marko; Mioč, Marija; Ester, Katja; Martin-Kleiner, Irena; Šumanovac Ramljak, Tatjana; Mlinarić-Majerski, Kata; Kralj, Marijeta (2018) Crown ethers reverse P-glycoprotein-mediated multidrug resistance in cancer cells. Scientific Reports, 8 (1). ISSN 2045-2322

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Abstract

Multidrug resistance (MDR) is a widespread phenomenon exhibited by many cancers and represents a fundamental obstacle for successful cancer treatments. Tumour cells commonly achieve MDR phenotype through overexpression and/or increased activity of ABC transporters. P-glycoprotein transporter (P-gp, ABCB1) is a major cause of MDR and therefore represents a valuable target for MDR reversal. Several naturally occurring potassium ionophores (e.g. salinomycin) were shown to inhibit P-gp effectively. We have previously shown antitumour activity of a number of 18- crown-6 ether compounds that transport potassium ions across membranes. Here we present data on P-gp inhibitory activity of 16 adamantane-substituted monoaza- and diaza-18- crown-6 ether compounds, and their effect on MDR reversal in model cell lines. We show that crown ether activity depends on their lipophilicity as well as on the linker to adamantane moiety. The most active crown ethers were shown to be more effective in sensitising MDR cells to paclitaxel and adriamycin than verapamil, a well-known P-gp inhibitor. Altogether our data demonstrate a novel use of crown ethers for inhibition of P-gp and reversal of MDR phenotype.

Item Type: Article
Uncontrolled Keywords: Crown-ethers; P-gp; MDR
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Division of Molecular Medicine
Division of Organic Chemistry and Biochemistry
Projects:
Project titleProject leaderProject codeProject type
Mulitidisciplinarni pristup otkriću lijekova s ciljanim djelovanjem na matične stanice tumora – uloga transporta kalija-MultiCaSTMarijeta KraljIP-2013-11-5660HRZZ
Depositing User: Marijeta Kralj
Date Deposited: 20 Dec 2018 12:51
Last Modified: 20 Dec 2018 12:53
URI: http://fulir.irb.hr/id/eprint/4387
DOI: 10.1038/s41598-018-32770-y

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