title: Anti-proliferative synergy of lysophospholipid analogues and ketoconazole against Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae): cellular and ultrastructural analysis.
abstract: OBJECTIVE
  Investigation of the antiproliferative synergy of the lysophospholipid analogues (LPAs) edelfosine, ilmofosine and miltefosine with the ergosterol biosynthesis inhibitor ketoconazole against Trypanosoma cruzi.
  
  
  METHODS
  The effect of LPAs, ketoconazole and their combination was evaluated against epimastigotes and intracellular amastigotes by the parameter IC50 leading to construction of isobolograms, for determination of a synergic effect. For epimastigotes, ultrastructural damage induced by these treatments was evaluated by transmission and scanning electron microscopy.
  
  
  RESULTS
  Synergy was confirmed against both epimastigotes and amastigotes of the parasite. Edelfosine or ketoconazole alone induced morphological alterations in the plasma membrane and reservosomes of the parasites, while in combination, they also led to severe mitochondrial damage, formation of autophagic structures and multinucleation. Scanning electron microscopy confirmed the effect at the plasma membrane and also revealed alterations in the shape of the parasites.
  
  
  CONCLUSIONS
  Our results describe the synergic anti-proliferative effect of LPAs and ketoconazole against epimastigotes and intracellular amastigotes and suggest that in epimastigotes, plasma membrane, reservosomes and mitochondria are targets of these drugs, possibly by interference with lipid metabolism.
authors.affiliation: Departmento de Ultra-estrutura e Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, CP 926, 21045-900, Rio de Janeiro, Brazil.
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Santa-Rita
authors.forename: Renee
authors.initials: R
authors.lastname: Lira
authors.forename: Helene Santos
authors.initials: HS
authors.lastname: Barbosa
authors.forename: Julio A
authors.initials: JA
authors.lastname: Urbina
authors.forename: Solange L
authors.initials: SL
authors.lastname: de Castro
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004875:Ergosterol / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007654:Ketoconazole / Q000494:pharmacology*; D008246:Lysophospholipids / Q000737:chemistry / Q000494:pharmacology*; D008854:Microscopy, Electron; D008855:Microscopy, Electron, Scanning; D021261:Parasitic Sensitivity Tests / Q000379:methods; D010742:Phospholipid Ethers / Q000494:pharmacology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000254:growth & development* / Q000648:ultrastructure; D014709:Vero Cells
chemical_list: D008246:Lysophospholipids; D010742:Phospholipid Ethers; D014344:Trypanocidal Agents; D010767:Phosphorylcholine; C026659:edelfosine; C039128:miltefosine; D007654:Ketoconazole; D004875:Ergosterol