The relationship between the gangliosides overexpression in tumor progression and the selectivity of anticancer drug – Edelfosine – The Langmuir monolayers study

Edelfosine is a synthetic ether lipid of high antitumor activity and low toxicity towards normal cells. This drug acts on membrane level as it incorporates into cancer membranes [1]. Studies on the mechanism of action of edelfosine proved its insertion into membrane microdomains [2], strong interactions with cholesterol [3] and easier incorporation into membranes of lower condensation [4]. To understand why edelfosine is active on tumor cells while it spares their normal counterparts, we have performed the Langmuir monolayer experiments, aimed at selecting the membrane component(s), which may be responsible for the selectivity of this drug. Because of the affinity of edelfosine to membrane rafts, in the first step of our investigations the interactions between edelfosine and sphingolipids (sphingomyelin and ganglioside GM1) were analyzed. Strong affinity of the drug molecules to GM1 ganglioside was found in the monolayer experiments. Since tumor progression is connected with overexpression of gangliosides, these findings stimulated our further research on more complex model membranes. Namely, into sphingomyelin/cholesterol/ganglioside model tumor membranes of increasing proportion of the ganglioside, edelfosine molecules in various concentration were incorporated. It was found that edelfosine in a low concentration (1%) practically does not influence on model membrane system, independently on the proportion of the ganglioside. However, when the concentration of edelfosine increases up to 10%, the interactions between the lipids become progressively stronger with the increase of ganglioside concentration. These results may suggest that gangliosides are important as the selectivity of edelfosine is concerned, because the concentration of these lipids in normal cells is very low, while their increase is observed with tumor progression.