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2025-01-01
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SELECTIVE IN VITRO EFFECTS OF THE FARNESYL PYROPHOSPHATE SYNTHASE INHIBITOR RISEDRONATE ON TRYPANOSOMA CRUZI
Doença de Chagas
Amastigote
Efeito antiproliferativo
Risedronato
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Ultra-estrutura e Biologia Celular. Rio de Janeiro, RJ, Brasil.
Instituto Venezolano de Investigaciones Cientificas. Centro de Biofísica y Bioquímica. Laboratorio de Química Biológica. Caracas, Venezuela.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Ultra-estrutura e Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Ultra-estrutura e Biologia Celular. Rio de Janeiro, RJ, Brasil.
University of Illinois at Urbana-Champaign. Center for Zoonoses Research. Department of Pathophisilogy. Laboratory of Molecular Parasitology. Urbana, IL, USA.
University of Illinois at Urbana-Champaign. Department of Biophysics. Department of Chemistry. Urbana, IL, USA.
niversity of Illinois at Urbana-Champaign. Department of Biophysics. Department of Chemistry. Urbana, IL, USA.
Instituto Venezolano de Investigaciones Cientificas. Centro de Biofísica y Bioquímica. Laboratorio de Química Biológica. Caracas, Venezuela.
Instituto Venezolano de Investigaciones Cientificas. Centro de Biofísica y Bioquímica. Laboratorio de Química Biológica. Caracas, Venezuela.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Ultra-estrutura e Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Ultra-estrutura e Biologia Celular. Rio de Janeiro, RJ, Brasil.
University of Illinois at Urbana-Champaign. Center for Zoonoses Research. Department of Pathophisilogy. Laboratory of Molecular Parasitology. Urbana, IL, USA.
University of Illinois at Urbana-Champaign. Department of Biophysics. Department of Chemistry. Urbana, IL, USA.
niversity of Illinois at Urbana-Champaign. Department of Biophysics. Department of Chemistry. Urbana, IL, USA.
Instituto Venezolano de Investigaciones Cientificas. Centro de Biofísica y Bioquímica. Laboratorio de Química Biológica. Caracas, Venezuela.
Abstract
We present the results of the first detailed study of the molecular and cellular basis of the antiproliferative effects of the bisphosphonate risedronate (Ris) on Trypanosoma cruzi, the causative agent of Chagas' disease. Ris and related compounds, which block poly-isoprenoid biosynthesis at the level of farnesyl pyrophosphate synthase, are currently used for the treatment of bone resorption disorders, but also display selective activity against trypanosomatid and apicomplexan parasites. Ris induced a dose-dependent effect on growth of the extracellular epimastigote form of T. cruzi; complete growth arrest and cell lysis ensued at 150 microM. Growth inhibition was associated with depletion of the parasite's endogenous sterols, but complete growth arrest and loss of cell viability took place before full depletion of these compounds, suggesting that disappearance of other essential poly-isoprenoids is involved in its anti-parasitic action. Ris had a variety of effects on cellular ultrastructure, including mitochondrial swelling, disorganisation of other organelles, such as reservosomes and the kinetoplast, together with the appearance of autophagic vesicles and progressive vacuolization of the cytoplasm. Ris had selective antiproliferative effects against the clinically relevant amastigote form of T. cruzi, and at 100 microM, was able to prevent completely the development of T. cruzi infection of murine muscle heart or Vero cells, and to cure cultures which were already infected. Ris induced drastic ultrastructural alterations in the intracellular parasites and blocked amastigote to trypomastigote differentiation, with no biochemical or ultrastructural effects on the host cells, which fully recovered their normal structure and activity after treatment. Ris is, therefore, a promising lead compound for the development of new drugs against T. cruzi.
Keywords in Portuguese
Trypanosoma cruziDoença de Chagas
Amastigote
Efeito antiproliferativo
Risedronato
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