Testing the hypothesis that amphiphilic antineoplastic lipid analogues act through reduction of membrane curvature elastic stress.

Abstract

The alkyllysophospholipid (ALP) analogues Mitelfosine and Edelfosine are anticancer drugs whose mode of action is still the subject of debate. It is agreed that the primary interaction of these compounds is with cellular membranes. Furthermore, the membrane-associated protein CTP: phosphocholine cytidylyltransferase (CCT) has been proposed as the critical target. We present the evaluation of our hypothesis that ALP analogues disrupt membrane curvature elastic stress and inhibit membrane-associated protein activity (e.g. CCT), ultimately resulting in apoptosis. This hypothesis was tested by evaluating structure-activity relationships of ALPs from the literature. In addition we characterized the lipid typology, cytotoxicity and critical micelle concentration of novel ALP analogues that we synthesized. Overall we find the literature data and our experimental data provide excellent support for the hypothesis, which predicts that the most potent ALP analogues will be type I lipids.