Miltefosine increases lipid and protein dynamics in Leishmania membranes at similar concentrations to those needed for cytotoxicity activity

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dc.creatorMoreira, Rodrigo Alves
dc.creatorMendanha Neto, Sebastião Antônio
dc.creatorFernandes, Kelly Souza
dc.creatorMatos, Grazzielle Guimaraes de
dc.creatorAlonso, Lais
dc.creatorDorta, Miriam Cristina Leandro
dc.creatorAlonso, Antonio
dc.date.accessioned2018-08-06T13:02:54Z
dc.date.available2018-08-06T13:02:54Z
dc.date.issued2014-06
dc.description.abstractMiltefosine (MT) is a membrane-active alkylphospholipid licensed for the topical treatment of breast cancer skin metastases and the oral treatment of leishmaniasis, although its mechanism of action remains unclear. Electron paramagnetic resonance (EPR) spectroscopy of a spin-labeled lipid and a thiol-specific spin label in the plasma membrane of Leishmania promastigotes showed that MT causes dramatic increases in membrane dynamics. Although these alterations can be detected using a spin-labeled lipid, our experimental results indicated that MT interacts predominantly with the protein component of the membrane. Cell lysis was also detected by analyzing the supernatants of centrifuged samples for the presence of spin-labeled membrane fragments and cytoplasmic proteins. Using a method for the rapid incorporation of MT into the membrane, these effects were measured imme- diately after treatment under the same range of MT concentrations that cause cell growth inhibition. Cytotoxicity, estimated via microscopic counting of living and dead cells, indicated ⬃70% cell death at the concentration of MT at which EPR spectroscopy detected a significant change in membrane dynamics. After this initial impact on the number of viable parasites, the processes of cell death and growth continued during the first 4 h of incubation. The EPR spectra of spin-labeled membrane-bound proteins were consistent with more expanded and solvent-exposed protein conformations, suggesting a detergent-like action. Thus, MT may form micelle-like structures around polypeptide chains, and proteins with a higher hydrophobicity may induce the penetra- tion of hydrophilic groups of MT into the membrane, causing its rupture.pt_BR
dc.identifier.citationMOREIRA, Rodrigo Alves; MENDANHA, Sebastião Antonio; FERNANDES, Kelly Souza; MATOS, Grazzielle Guimaraes; ALONSO, Lais; DORTA, Miriam Leandro; ALONSO, Antonio. Miltefosine increases lipid and protein dynamics in Leishmania membranes at similar concentrations to those needed for cytotoxicity activity. Antimicrobial Agents and Chemotherapy, Washington, v. 58, n. 6, p. 3021-3028, Jun. 2014.pt_BR
dc.identifier.doi10.1128/AAC.01332-13
dc.identifier.issn0066-4804
dc.identifier.issne- 1098-6596
dc.identifier.urihttp://repositorio.bc.ufg.br/handle/ri/15559
dc.language.isoengpt_BR
dc.publisher.countryEstados unidospt_BR
dc.publisher.departmentInstituto de Patologia Tropical e Saúde Pública - IPTSP (RG)pt_BR
dc.rightsAcesso Abertopt_BR
dc.titleMiltefosine increases lipid and protein dynamics in Leishmania membranes at similar concentrations to those needed for cytotoxicity activitypt_BR
dc.typeArtigopt_BR

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