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.
Highlights
Multidrug resistance (MDR) is a phenomenon that describes cross-resistance of cancer cells to a broad range of structurally diverse chemotherapeutics
Cancer stem cell (CSC) resistance to chemo- and radiotherapy arises from several different mechanisms, which include increased expression of ATP-binding cassette (ABC) drug efflux pumps (e.g. P-gp, ABCG2)[5,6,7]
We identified significant cytotoxicity of these novel crown ethers towards five different cancer cell types[17,18,19]
Summary
Multidrug resistance (MDR) is a phenomenon that describes cross-resistance of cancer cells to a broad range of structurally diverse chemotherapeutics. P-glycoprotein (P-gp) belongs to the ABC transporter superfamily and is encoded by ABCB1, known as multidrug resistance 1 (MDR1) gene. This 170 kDa transmembrane protein is mainly localized in the plasma membrane where it acts as an efflux transporter for a wide variety of structurally and chemically diverse substances. CSCs resistance to chemo- and radiotherapy arises from several different mechanisms, which include increased expression of ABC drug efflux pumps (e.g. P-gp, ABCG2)[5,6,7]. The main function of ionophores is their ability to transport ions across lipid membranes This leads to disrupting cell membrane potential and ion homeostasis, which results in physiological and osmotic stress. Various natural ionophores (e.g. salinomycin, nigericin, valinomycin) are used as antibiotics, and more recently in cancer treatment[10,11,12,13]
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