Selective in vitro effects of the farnesyl pyrophosphate synthase inhibitor risedronate on Trypanosoma cruzi.
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.
Garzoni
Luciana R
LR
Departmento de Ultra-estrutura e Biologia Celular, Instituto Oswaldo Cruz, Av. Brasil, 4365, Manguinhos, 21045-900 Rio de Janeiro, RJ, Brazil.
Caldera
Aura
A
Meirelles
Maria de Nazareth L
Mde N
de Castro
Solange L
SL
Docampo
Roberto
R
Meints
Gary A
GA
Oldfield
Eric
E
Urbina
Julio A
JA
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002478:Cells, Cultured; D014355:Chagas Disease / Q000517:prevention & control; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051228:Geranyltranstransferase; D051379:Mice; D008854:Microscopy, Electron; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000469:parasitology / Q000473:pathology; D000068296:Risedronic Acid; D013261:Sterols / Q000378:metabolism; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure; D014709:Vero Cells
D004791:Enzyme Inhibitors; D013261:Sterols; D014344:Trypanocidal Agents; D019883:Alkyl and Aryl Transferases; D051228:Geranyltranstransferase; D000068296:Risedronic Acid; D012968:Etidronic Acid