title: Terpenes increase the lipid dynamics in the Leishmania plasma membrane at concentrations similar to their IC50 values.
abstract: Although many terpenes have shown antitumor, antibacterial, antifungal, and antiparasitic activity, the mechanism of action is not well established. Electron paramagnetic resonance (EPR) spectroscopy of the spin-labeled 5-doxyl stearic acid revealed remarkable fluidity increases in the plasma membrane of terpene-treated Leishmania amazonensis promastigotes. For an antiproliferative activity assay using 5×10(6) parasites/mL, the sesquiterpene nerolidol and the monoterpenes (+)-limonene, α-terpineol and 1,8-cineole inhibited the growth of the parasites with IC50 values of 0.008, 0.549, 0.678 and 4.697 mM, respectively. The IC50 values of these terpenes increased as the parasite concentration used in the cytotoxicity assay increased, and this behavior was examined using a theoretical treatment of the experimental data. Cytotoxicity tests with the same parasite concentration as in the EPR experiments revealed a correlation between the IC50 values of the terpenes and the concentrations at which they altered the membrane fluidity. In addition, the terpenes induced small amounts of cell lysis (4-9%) at their respective IC50 values. For assays with high cell concentrations (2×10(9) parasites/mL), the incorporation of terpene into the cell membrane was very fast, and the IC50 values observed for 24 h and 5 min-incubation periods were not significantly different. Taken together, these results suggest that terpene cytotoxicity is associated with the attack on the plasma membrane of the parasite. The in vitro cytotoxicity of nerolidol was similar to that of miltefosine, and nerolidol has high hydrophobicity; thus, nerolidol might be used in drug delivery systems, such as lipid nanoparticles to treat leishmaniasis.
authors.affiliation: Instituto de Física, Universidade Federal de Goiás, Goiânia, GO, Brazil; Engenharia Elétrica, Fundação Universidade Federal do Tocantins, Palmas, TO, Brasil.
authors.forename: Heverton Silva
authors.initials: HS
authors.lastname: Camargos
authors.affiliation: Instituto de Física, Universidade Federal de Goiás, Goiânia, GO, Brazil.
authors.forename: Rodrigo Alves
authors.initials: RA
authors.lastname: Moreira
authors.affiliation: Instituto de Física, Universidade Federal de Goiás, Goiânia, GO, Brazil.
authors.forename: Sebastião Antonio
authors.initials: SA
authors.lastname: Mendanha
authors.affiliation: Instituto de Física, Universidade Federal de Goiás, Goiânia, GO, Brazil.
authors.forename: Kelly Souza
authors.initials: KS
authors.lastname: Fernandes
authors.affiliation: Instituto de Patologia Tropical e Saúde Publica, Departamento de Imunologia e Patologia Geral, Universidade Federal de Goiás, Goiânia, GO, Brazil.
authors.forename: Miriam Leandro
authors.initials: ML
authors.lastname: Dorta
authors.affiliation: Instituto de Física, Universidade Federal de Goiás, Goiânia, GO, Brazil.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alonso
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D053138:Cyclohexenes / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004578:Electron Spin Resonance Spectroscopy; D007891:Leishmania / Q000378:metabolism*; D007896:Leishmaniasis / Q000178:diet therapy / Q000378:metabolism; D000077222:Limonene; D008563:Membrane Lipids / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D013729:Terpenes / Q000494:pharmacology*
chemical_list: D053138:Cyclohexenes; D008563:Membrane Lipids; D012717:Sesquiterpenes; D013729:Terpenes; D000077222:Limonene; C037055:nerolidol
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