Abstract
Alkylphospholipids are a novel class of antineoplastic drugs showing remarkable therapeutic potential. Among them, erufosine (EPC3) is a promising drug for the treatment of several types of tumors. While EPC3 is supposed to exert its function by interacting with lipid membranes, the exact molecular mechanisms involved are not known yet. In this work, we applied a combination of several fluorescence microscopy and analytical chemistry approaches (i.e., scanning fluorescence correlation spectroscopy, line-scan fluorescence correlation spectroscopy, generalized polarization imaging, as well as thin layer and gas chromatography) to quantify the effect of EPC3 in biophysical models of the plasma membrane, as well as in cancer cell lines. Our results indicate that EPC3 affects lipid–lipid interactions in cellular membranes by decreasing lipid packing and increasing membrane disorder and fluidity. As a consequence of these alterations in the lateral organization of lipid bilayers, the diffusive dynamics of membrane proteins are also significantly increased. Taken together, these findings suggest that the mechanism of action of EPC3 could be linked to its effects on fundamental biophysical properties of lipid membranes, as well as on lipid metabolism in cancer cells.
Highlights
Erufosine (EPC3) is a novel derivate of erucylphosphocholine that belongs to a group of antineoplastic drugs based on alkyl ether lipids [1]
As a consequence of these alterations in the lateral organization of lipid bilayers, the diffusive dynamics of membrane proteins are significantly increased. These findings suggest that the mechanism of action of EPC3 could be linked to its effects on fundamental biophysical properties of lipid membranes, as well as on lipid metabolism in cancer cells
In order to assess the influence of EPC3 on lipid–lipid interactions, first, we investigated its effects on controlled membrane models
Summary
Erufosine (EPC3) is a novel derivate of erucylphosphocholine that belongs to a group of antineoplastic drugs based on alkyl ether lipids [1]. It was shown that edelfosine, which was one of the first characterized APLs, induced apoptosis in cancer cells via interactions with lipid rafts [1], i.e., lipid-protein domains of the plasma membrane (PM) which are enriched in sphingolipids and cholesterol [3,4,5] and are involved in several cellular functions (see e.g., [6,7]). Such domains can be characterized in protein-free model membrane systems (e.g., lipid vesicles) constituted of typical PM lipids (e.g., saturated sphingomyelin (SM), unsaturated phosphatidylcholine (PC), and cholesterol). Studies on erucylphosphocholine (which is more similar to EPC3, due to the shared unsaturated acyl chain structure) have indicated that this APL increases the fluidity of both cellular and model membranes [12], while weakening SM–cholesterol interactions [15]
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