Anti-proliferative synergy of lysophospholipid analogues and ketoconazole against Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae): cellular and ultrastructural analysis

Submitted by Sandra Infurna ([email protected]) on 2019-12-10T17:33:52Z No. of bitstreams: 1 RicardoSantaRita_HeleneBarbosa_etal_IOC_2005.pdf: 239835 bytes, checksum: 1dc2d1230a3762a8343f54772eb4e797 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2019-12-10T17:46:02Z (GMT) No. of bitstreams: 1 RicardoSantaRita_HeleneBarbosa_etal_IOC_2005.pdf: 239835 bytes, checksum: 1dc2d1230a3762a8343f54772eb4e797 (MD5)Made available in DSpace on 2019-12-10T17:46:02Z (GMT). No. of bitstreams: 1 RicardoSantaRita_HeleneBarbosa_etal_IOC_2005.pdf: 239835 bytes, checksum: 1dc2d1230a3762a8343f54772eb4e797 (MD5) Previous issue date: 2005Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departmento de Ultra-estrutura e Biologia Celular. Rio de Janeiro, RJ, Brasil.Instituto Venezolano de Investigaciones Científicas. Centro de Biofísica y Bioquímica. Laboratório de Química Biológica. Caracas, Venezuela.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departmento de Ultra-estrutura e Biologia Celular. Rio de Janeiro, RJ, Brasil.Instituto Venezolano de Investigaciones Científicas. Centro de Biofísica y Bioquímica. Laboratório de Química Biológica. Caracas, Venezuela.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departmento de Ultra-estrutura e Biologia Celular. Rio de Janeiro, RJ, Brasil.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

Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole

There is no effective treatment for the prevalent chronic form of Chagas' disease in Latin America. Its causative agent, the protozoan parasite Trypanosoma cruzi, has an essential requirement for ergosterol, and ergosterol biosynthesis inhibitors, such as the antifungal drug posaconazole, have potent trypanocidal activity. The antiarrhythmic compound amiodarone, frequently prescribed for the symptomatic treatment of Chagas' disease patients, has also recently been shown to have antifungal activity. We now show here for the first time that amiodarone has direct activity against T. cruzi, both in vitro and in vivo, and that it acts synergistically with posaconazole. We found that amiodarone, in addition to disrupting the parasites' Ca2+ homeostasis, also blocks ergosterol biosynthesis, and that posaconazole also affects Ca2+ homeostasis. These results provide logical explanations for the synergistic activity of amiodarone with azoles against T. cruzi and open up the possibility of novel, combination therapy approaches to the treatment of Chagas' disease using currently approved drugs.Fil: Benaim, Gustavo. Universidad Central de Venezuela, Facultad de Ciencias; Venezuela. Instituto Internacional de Estudios Avanzados; VenezuelaFil: Sanders, John M.. University of Illinois at Urbana; Estados UnidosFil: Garcia Marchán, Yael. Universidad Central de Venezuela, Facultad de Ciencias; VenezuelaFil: Colina, Claudia. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Lira, Renee. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Caldera, Aura R.. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Payares, Gilberto. Universidad Central de Venezuela. Facultad de Ciencias; VenezuelaFil: Sanoja, Cristina. Universidad Central de Venezuela. Facultad de Ciencias; VenezuelaFil: Burgos, Juan Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Leon-Rossell, Annette. University of Illinois. Urbana - Champaign; Estados UnidosFil: Concepcion, Juan Luis. Universidad de los Andes; VenezuelaFil: Schijman, Alejandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Levin, Mariano Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Institut Cochin; FranciaFil: Oldfield, Eric. University of Illinois. Urbana - Champaign; Estados UnidosFil: Urbina, Julio A.. Instituto Venezolano de Investigaciones Científicas; Venezuel