engleski

Crown ether compound 613 as a small molecule with good antitumor potential: investigation of membrane perturbation and changes in ion homeostasis

Crown ethers represent small molecules that hold promising antitumor potential. Among other modes of action, crown ethers can act as ionophores, i.e. disturbing ion homeostasis and disrupting biological membranes. We showed that crown ethers inhibit P-glycoprotein and reverse the multidrug resistance in cancer cells. Based on the previous in vitro screening, we identified the proprietary crown ether compound 613 as a potential antitumor drug. Inhibition of tumor growth was confirmed on the panel of breast tumor cells, and in an in vivo mouse model. To unravel the mechanism of action, we choose an approach based on its structure: we postulated that 613 could 1) potentially bind and move ions through the membrane and change the ion homeostasis, and 2) cause perturbations of the lipid membranes throughout the cell due to its hydrophobicity. We found that compound 613 induced K+ and Na+ fluxes and modulated resting potential of cells. Physical disturbance of lipid membranes throughout the cell was demonstrated by increase in plasma membrane permeability and impairment of mitochondrial functions. The importance and/or interplay of the two mechanisms responsible for cytotoxicity yet awaits to be resolved.

crown ether ; breast cancer ; membrane potential ; cell death ; ionophore

nije evidentirano