title: Edelfosine and miltefosine effects on lipid raft properties: membrane biophysics in cell death by antitumor lipids.
abstract: Edelfosine (1-O-octadecyl-2-O-methyl-sn-glycero-phosphocholine) and miltefosine (hexadecylphosphocholine) are synthetic alkylphospholipids (ALPs) that are reported to selectively accumulate in tumor cell membranes, inducing Fas clustering and activation on lipid rafts, triggering apoptosis. However, the exact mechanism by which these lipids elicit these events is still not fully understood. Recent studies propose that their mode of action might be related with alterations of lipid rafts biophysical properties caused by these lipid drugs. To achieve a clear understanding of this mechanism, we studied the effects of pharmacologically relevant amounts of edelfosine and miltefosine in the properties of model and cellular membranes. The influence of these molecules on membrane order, lateral organization, and lipid rafts molar fraction and size were studied by steady-state and time-resolved fluorescence methods, Förster resonance energy transfer (FRET), confocal and fluorescence lifetime imaging microscopy (FLIM). We found that the global membrane and lipid rafts biophysical properties of both model and cellular membranes were not significantly affected by both the ALPs. Nonetheless, in model membranes, a mild increase in membrane fluidity induced by both alkyl lipids was detected, although this effect was more noticeable for edelfosine than miltefosine. This absence of drastic alterations shows for the first time that ALPs mode of action is unlikely to be directly linked to alterations of lipid rafts biophysical properties caused by these drugs. The biological implications of this result are discussed in the context of ALPs effects on lipid metabolism, mitochondria homeostasis modulation, and their relationship with tumor cell death.
authors.affiliation: Centro de Química Física-Molecular and Institute of Nanoscience and Nanotechnology, IST, Universidade Técnica de Lisboa , Av. Rovisco Pais, 1049-001 Lisboa, Portugal. bruno.castro@icfo.es
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Castro
authors.forename: Aleksander
authors.initials: A
authors.lastname: Fedorov
authors.forename: Valentin
authors.initials: V
authors.lastname: Hornillos
authors.forename: Javier
authors.initials: J
authors.lastname: Delgado
authors.forename: A Ulises
authors.initials: AU
authors.lastname: Acuña
authors.forename: Faustino
authors.initials: F
authors.lastname: Mollinedo
authors.forename: Manuel
authors.initials: M
authors.lastname: Prieto
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D008081:Liposomes / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism; D010742:Phospholipid Ethers / Q000494:pharmacology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D010742:Phospholipid Ethers; D010767:Phosphorylcholine; C026659:edelfosine; C039128:miltefosine