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Título : | Ergosterone-coupled Triazol molecules trigger mitochondrial dysfunction, oxidative stress, and acidocalcisomal Ca2+ release in Leishmania mexicana promastigotes |
Autor : | Figarella, K. Marsicobetre, S. Colina, W. Hasegawa, Masahisa Rodríguez, María del C. Rodríguez-Acosta, A. Duszenko, M. Benaím, Gustavo Uzcategui, NL |
Palabras clave : | Leishmania ergosterol azoles cell death autophagy ROS Ca2+ |
Fecha de publicación : | 2016 |
Editorial : | Microbial Cell |
Citación : | Vol. 3, No. 1, pp 14-28 |
Resumen : | The protozoan parasite Leishmania causes a variety of sicknesses
with different clinical manifestations known as leishmaniasis. The chemotherapy
currently in use is not adequate because of their side effects, resistance
occurrence, and recurrences. Investigations looking for new targets
or new active molecules focus mainly on the disruption of parasite specific
pathways. In this sense, ergosterol biosynthesis is one of the most attractive
because it does not occur in mammals. Here, we report the synthesis of ergosterone
coupled molecules and the characterization of their biological activity
on Leishmania mexicana promastigotes. Molecule synthesis involved
three steps: ergosterone formation using Jones oxidation, synthesis of Girard
reagents, and coupling reaction. All compounds were obtained in good yield
and high purity. Results show that ergosterone-triazol molecules (Erg-GTr and
Erg-GTr2) exhibit an antiproliferative effect in low micromolar range with a
selectivity index ~10 when compared to human dermic fibroblasts. Addition
of Erg-GTr or Erg-GTr2 to parasites led to a rapid [Ca2+]cyt increase and acidocalcisomes
alkalinization, indicating that Ca2+ was released from this organelle.
Evaluation of cell death markers revealed some apoptosis-like indicators,
as phosphatidylserine exposure, DNA damage, and cytosolic vacuolization
and autophagy exacerbation. Furthermore, mitochondrion hyperpolarization
and superoxide production increase were detected already 6 hours
after drug addition, denoting that oxidative stress is implicated in triggering
the observed phenotype. Taken together our results indicate that ergosterone-
triazol coupled molecules induce a regulated cell death process in the
parasite and may represent starting point molecules in the search of new
chemotherapeutic agents to combat leishmaniasis. |
URI : | http://hdl.handle.net/10872/14210 |
ISSN : | 2311-2638 |
Aparece en las colecciones: | Artículos Publicados
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