Crown ethers reverse P-glycoprotein-mediated multidrug resistance in cancer cells
Iva Guberović1,2, Marko Marjanović1, Marija Mioč1
1Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10 000, Zagreb, Croatia.
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.
Insights
New crown ether compounds effectively inhibit P-glycoprotein (P-gp), a key factor in multidrug resistance (MDR). These compounds reverse MDR in cancer cells, offering a promising strategy against drug-resistant tumors.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Multidrug resistance (MDR) in cancer hinders effective treatment.
- Overexpression of ABC transporters, like P-glycoprotein (P-gp), drives MDR.
- P-gp is a significant target for overcoming MDR.
Purpose of the Study:
- To evaluate adamantane-substituted 18-crown-6 ether compounds as P-gp inhibitors.
- To assess their efficacy in reversing MDR in cancer cell lines.
- To explore structure-activity relationships influencing P-gp inhibition.
Main Methods:
- Synthesis and characterization of 16 novel adamantane-substituted monoaza- and diaza-18-crown-6 ethers.
- Assessment of P-gp inhibitory activity in model cell lines.
- Evaluation of MDR reversal in cells treated with paclitaxel and adriamycin.
Main Results:
- Crown ether activity correlated with lipophilicity and linker structure.
- The most potent crown ethers demonstrated superior MDR reversal compared to verapamil.
- Several compounds effectively sensitized MDR cells to common chemotherapeutics.
Conclusions:
- Adamantane-substituted 18-crown-6 ethers are effective P-gp inhibitors.
- These novel compounds represent a promising new class for MDR reversal strategies.
- Crown ethers offer a viable therapeutic avenue for overcoming multidrug resistance in cancer.
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