title: Interaction of miltefosine with the lipid and protein components of the erythrocyte membrane.
abstract: Miltefosine (MT) is an alkylphospholipid that has been approved for the treatment of breast cancer metastasis and visceral leishmaniasis, although its mechanism of action remains poorly understood. Electron paramagnetic resonance spectroscopy of a spin-labeled lipid and a thiol-specific spin label showed that MT causes an increase in the molecular dynamics of erythrocyte ghost membranes and detergent-resistant membranes (DRMs) prepared from erythrocyte ghosts. In the vesicles of lipid raft constituents, it was shown that 20 mol % sphingomyelin could be replaced by 20 mol % MT with no change in the molecular dynamics. The effect of MT in DRMs was more pronounced than in erythrocyte ghosts, supporting the hypothesis that MT is a lipid raft modulator. At the reported MT-plasma concentrations found during the treatment of leishmaniasis (31-90 µg/mL), our measurements in the blood plasma indicated a hemolytic level of 2%-5%. The experiments indicated that MT acts predominantly on the protein component of the membrane. MT aggregates may wrap around the hydrophobic polypeptide chains, forming micelle-like structures that stabilize protein conformations more exposed to the solvent. Proteins with higher hydrophobicity may induce the penetration of the hydrophilic groups of MT into the membrane and cause it to rupture.
authors: Instituto de Física, Universidade Federal de Goiás, Goiânia, GO, Brazil.
authors: Rodrigo Alves
authors: RA
authors: Moreira
authors: Sebastião Antonio
authors: SA
authors: Mendanha
authors: Daiane
authors: D
authors: Hansen
authors: Antonio
authors: A
authors: Alonso
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism*; D000981:Antiprotozoal Agents / Q000097:blood / Q000378:metabolism*; D004910:Erythrocyte Membrane / Q000187:drug effects* / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000981:Antiprotozoal Agents; D008563:Membrane Lipids; D008565:Membrane Proteins; D010767:Phosphorylcholine; C039128:miltefosine