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

Journal of the Royal Society, Interface
Marcus K DymondAnthony D Postle

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.

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Citations

Dec 21, 2012·Journal of the Royal Society, Interface·Marcus K DymondGeorge S Attard
Jun 26, 2010·Journal of the American Chemical Society·Camilla F BlackGeorge S Attard
Aug 3, 2013·Biochimica Et Biophysica Acta·Michał FlasińskiPatrycja Dynarowicz-Łątka
Jun 24, 2017·Biochimica Et Biophysica Acta. Biomembranes·Yenisleidy de Las Mercedes Zulueta Díaz, María Laura Fanani
Dec 15, 2010·The Journal of Pharmacology and Experimental Therapeutics·Pablo Ríos-MarcoMaría P Carrasco
Nov 25, 2015·Toxicology Research·Prachi VermaK Indira Priyadarsini
Nov 25, 2020·International Journal of Molecular Sciences·Wendy S SmithDavid J Flavell
Jul 16, 2021·Chemistry and Physics of Lipids·Marcus K Dymond

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