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

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.

• Authors: Iva Guberović, Marko Marjanović, Marija Mioč, Katja Ester, Irena Martin-Kleiner, Tatjana Šumanovac Ramljak, Kata Mlinarić-Majerski, Marijeta Kralj
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 14467 (09 27 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 30262858 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Crown Ethers
• Vincristine
• 18-crown-6
• Doxorubicin
• Paclitaxel
• Potassium

Topics

• ATP Binding Cassette Transporter, Subfamily B (antagonists & inhibitors, metabolism)
• Animals
• Cell Line, Tumor
• Cell Membrane (metabolism, pathology)
• Crown Ethers (chemistry, pharmacology)
• Dogs
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Ion Transport (drug effects)
• Madin Darby Canine Kidney Cells
• Neoplasms (drug therapy, metabolism, pathology)
• Paclitaxel (pharmacology)
• Potassium (metabolism)
• Vincristine (pharmacology)