OBJECTIVES: 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.
OBJECTIVES: 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: Michael Duszenko; Michael L Ginger; Ana Brennand; Melisa Gualdrón-López; María Isabel Colombo; Graham H Coombs; Isabelle Coppens; Bamini Jayabalasingham; Gordon Langsley; Solange Lisboa de Castro; Rubem Menna-Barreto; Jeremy C Mottram; Miguel Navarro; Daniel J Rigden; Patricia S Romano; Veronika Stoka; Boris Turk; Paul A M Michels Journal: Autophagy Date: 2011-02-01 Impact factor: 16.016
Authors: R F S Menna-Barreto; G A T Laranja; M C C Silva; M G P Coelho; M C Paes; M M Oliveira; S L de Castro Journal: Parasitol Res Date: 2008-06 Impact factor: 2.289
Authors: Rafael Luis Kessler; Maurilio José Soares; Christian Macagnan Probst; Marco Aurélio Krieger Journal: PLoS One Date: 2013-01-31 Impact factor: 3.240