title: Disruption of lipid domain organization in monolayers of complex yeast lipid extracts induced by the lysophosphatidylcholine analogue edelfosine in vivo.
abstract: The lysophosphatidylcholine analogue edelfosine is a potent antitumor and antiparasitic drug that targets cell membranes. Previous studies have shown that edelfosine alters membrane domain organization inducing internalization of sterols and endocytosis of plasma membrane transporters. These early events affect signaling pathways that result in cell death. It has been shown that edelfosine preferentially partitions into more rigid lipid domains in mammalian as well as in yeast cells. In this work we aimed at investigating the effect of edelfosine on membrane domain organization using monolayers prepared from whole cell lipid extracts of cells treated with edelfosine compared to control conditions. In Langmuir monolayers we were able to detect important differences to the lipid packing of the membrane monofilm. Domain formation visualized by means of Brewster angle microscopy also showed major morphological changes between edelfosine treated versus control samples. Importantly, edelfosine resistant cells defective in drug uptake did not display the same differences. In addition, co-spread samples of control lipid extracts with edelfosine added post extraction did not fully mimic the results obtained with lipid extracts from treated cells. Altogether these results indicate that edelfosine induces changes in membrane domain organization and that these changes depend on drug uptake. Our work also validates the use of monolayers derived from complex cell lipid extracts combined with Brewster angle microscopy, as a sensitive approach to distinguish between conditions associated with susceptibility or resistance to lysophosphatidylcholine analogues.
authors.affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Mahadeo
authors.affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Safia
authors.initials: S
authors.lastname: Nathoo
authors.affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Suriakarthiga
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Driedger
authors.affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada. Electronic address: vzarembe@ucalgary.ca.
authors.forename: Vanina
authors.initials: V
authors.lastname: Zaremberg
authors.affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada. Electronic address: eprenner@ucalgary.ca.
authors.forename: Elmar J
authors.initials: EJ
authors.lastname: Prenner
mesh_terms: D002462:Cell Membrane / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D019245:Compressive Strength; D004705:Endocytosis; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010742:Phospholipid Ethers / Q000737:chemistry* / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000254:growth & development / Q000378:metabolism*
chemical_list: D010726:Phosphodiesterase Inhibitors; D010742:Phospholipid Ethers; C026659:edelfosine
keywords: Antitumor lipids; Brewster angle microscopy (BAM); Lipid domains; Lysophospholipid; Monolayer; Saccharomyces cerevisiae