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Tipo do documento: Artigo
Título: Miltefosine increases lipid and protein dynamics in Leishmania membranes at similar concentrations to those needed for cytotoxicity activity
Autor: Moreira, Rodrigo Alves
Mendanha Neto, Sebastião Antônio
Fernandes, Kelly Souza
Matos, Grazzielle Guimaraes de
Alonso, Lais
Dorta, Miriam Cristina Leandro
Alonso, Antonio
Abstract: Miltefosine (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.
País: Estados unidos
Unidade acadêmica: Instituto de Patologia Tropical e Saúde Pública - IPTSP (RG)
Citação: MOREIRA, 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.
Tipo de acesso: Acesso Aberto
Identificador do documento: 10.1128/AAC.01332-13
Identificador do documento: 10.1128/AAC.01332-13
Data de publicação: Jun-2014
Aparece nas coleções:IPTSP - Artigos publicados em periódicos

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