TY - JOUR
T1 - Selective in vitro effects of the farnesyl pyrophosphate synthase inhibitor risedronate on Trypanosoma cruzi
AU - Garzoni, Luciana R.
AU - Caldera, Aura
AU - Meirelles, Maria De Nazareth L.
AU - De Castro, Solange L.
AU - Docampo, Roberto
AU - Meints, Gary A.
AU - Oldfield, Eric
AU - Urbina, Julio A.
N1 - Funding Information:
We are grateful to Dr. Maurı́lio, J. Soares for the critical reading of this manuscript, Dr. Andrea Henriques-Pons and Ricardo M. Santa-Rita for the support on the flow cytometry analysis, to Bernardo Visentin for his excellent technical assistance. This work was supported with grants from FIOCRUZ, CNPq and FAPERJ, and the Howard Hughes Medical Institute (Grant 55000620 to J.U.) and in part by the US Public Health Service (NIH grant GM 65307 to E.O. and R.D.; NIH NRSA grant GM 65782 to G.A.M.) and by the American Heart Association, Midwest Affiliate (E.O.) and National Center (R.D.).
PY - 2004/3
Y1 - 2004/3
N2 - 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 μM. 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 μM, 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.
AB - 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 μM. 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 μM, 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.
KW - Amastigote
KW - Antiproliferative effect
KW - Chagas' disease
KW - Risedronate
KW - T. cruzi
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U2 - 10.1016/j.ijantimicag.2003.07.020
DO - 10.1016/j.ijantimicag.2003.07.020
M3 - Article
C2 - 15164969
AN - SCOPUS:1442336494
SN - 0924-8579
VL - 23
SP - 273
EP - 285
JO - International Journal of Antimicrobial Agents
JF - International Journal of Antimicrobial Agents
IS - 3
ER -