engleski

Crown ethers are able to reverse multidrug resistance and affect mitochondrial function in cancer cells

Multidrug resistance (MDR) is commonly known characteristic of many cancers and plays an important role in cancer treatment. Overexpression of ATP binding cassette (ABC) transporters called ABCB1 (MDR1/P-glycoprotein) and ABCG2 (BCRP) by cancer cells is responsible for this phenomenon, which makes this group of proteins a valuable target for cancer therapy by reversal of MDR. Salinomycin, naturally occurring potassium (K+) ionophore, was shown to inhibit P-gp transporter and to reverse MDR effectively. Salinomycin is a K+/H+ exchanger that can affect cation transport across different cellular membranes and thus impact on membranes’ bioenergetic performance, including mitochondrial membrane polarization and function. Based on the above-mentioned studies and anticancer activity of crown-ethers that act as K+ ionophores (previously published by our group), we showed that these compounds exhibit inhibitory effect towards ABC transporters, disrupt the potassium transport and modulate mitochondrial membrane transport as well. In this study, we showed the effect of adamantane-substituted monoaza- and diaza-18- crown-6 ether compounds on MDR reversal and their effect on mitochondrial membrane function, depending on their lipophilicity as well as on the chemical structure of the linker to adamantane moiety. Compounds that showed as the most potent P-gp and ABCG2 inhibitors were able to sensitize cancer cells to conventional chemotherapeutics paclitaxel and mitoxantrone, the substrates of P-gp and ABCG2 transporters, respectively. These data are promising and demonstrate a potential use of crown ethers in cancer therapy, by their ability to reverse MDR.

Multidrug resistance ; ABC transporters ; P-glycoprotein ; ABCG2 ; Crown ethers

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