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Título : | Amiodarone Destabilizes Intracellular Ca2+ Homeostasis and Biosynthesis of Sterols in Leishmania mexicana |
Autor : | Serrano-Martín, Xenón García-Marchan, Yael Fernandez, Alexis Rodríguez, Noris Rojas, Hector Visbal, Gonzalo Benaím, Gustavo |
Palabras clave : | Leishmaniasis public health glucantime pentostan toxic effects Trypanosoma cruzi |
Fecha de publicación : | 2009 |
Editorial : | ANTIMICROBIAL AGENTS AND CHEMOTHERAPY |
Citación : | Vol. 53, No. 4, pp. 1403–1410 |
Resumen : | lucantime and pentostan, which generate toxic effects in treated patients. We have recently shown that
amiodarone, frequently used as an antiarrhythmic, possesses activity against Trypanosoma cruzi through the
disruption of mitochondrial Ca2 homeostasis and the inhibition of parasite ergosterol biosynthesis, specifically
at the level of oxidosqualene cyclase activity (G. Benaim, J. Sanders, Y. Garcia-Marchan, C. Colina, R.
Lira, A. Caldera, G. Payares, C. Sanoja, J. Burgos, A. Leon-Rossell, J. Concepcion, A. Schijman, M. Levin, E.
Oldfield, and J. Urbina, J. Med. Chem. 49:892–899, 2006). Here we show that at therapeutic concentrations,
amiodarone has a profound effect on the viability of Leishmania mexicana promastigotes. Additionally, its effect
on the viability of the parasite was greater against intracellular amastigotes than against promastigotes, and
it did not affect the host cell. Using fluorimetric and confocal microscopy techniques, we also demonstrated that
the mechanism of action of amiodarone was related to the disruption of intracellular Ca2 homeostasis
through a direct action not only on the mitochondria but also on the acidocalcisomes. On the other hand,
analysis of the free sterols in promastigotes incubated with amiodarone showed that this drug also affected the
biosynthesis of 5-dehydroepisterol, which results in squalene accumulation, thus suggesting that amiodarone
inhibits the squalene epoxidase activity of the parasite. Taken together, the results obtained in the present work
point to a more general effect of amiodarone in trypanosomatids, opening potential therapeutic possibilities for
this infectious disease. |
URI : | http://hdl.handle.net/10872/4637 |
ISSN : | 0066-4804 doi:10.1128/AAC.01215-08 |
Aparece en las colecciones: | Artículos Publicados
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