Calcium Ionophore, Calcimycin, Kills Leishmania Promastigotes by Activating Parasite Nitric Oxide Synthase

0486302 - ÚMG 2018 RIV US eng J - Journal Article
Grekov, Igor - Pombinho, António R. - Kobets, Tetyana - Bartůněk, Petr - Lipoldová, Marie
Calcium Ionophore, Calcimycin, Kills Leishmania Promastigotes by Activating Parasite Nitric Oxide Synthase.
BioMed Research International. podzim, podzim (2017), č. článku 1309485. ISSN 2314-6133. E-ISSN 2314-6141
R&D Projects: GA ČR(CZ) GA14-30186S; GA ČR GA16-22346S; GA ČR GP14-35944P; GA ČR GP13-41002P; GA MŠMT LO1220; GA MŠMT LM2015063; GA MŠMT(XE) CZ.2.16/3.1.00/28026; GA MŠMT(XE) CZ.2.16/3.1.00/28026
Institutional support: RVO:68378050
Keywords : transmission
OECD category: Biochemistry and molecular biology
Impact factor: 2.583, year: 2017

Leishmaniasis is an infectious disease caused by protozoan parasites of the genus Leishmania. There is no vaccine against human leishmaniasis and the treatment of the disease would benefit from a broader spectrum and a higher efficacy of leishmanicidal compounds. We analyzed the leishmanicidal activity and the mechanism of action of the calcium ionophore, calcimycin. L. major promastigotes were coincubated with calcimycin and the viability of the cells was assessed using resazurin assay. Calcimycin displayed dose-dependent effect with IC50 = 0.16 mu M. Analysis of propidium iodide/LDS-751 stained promastigotes revealed that lower concentrations of calcimycin had cytostatic effect and higher concentrations had cytotoxic effect. To establish the mechanism of action of calcimycin, which is known to stimulate activity of mammalian constitutive nitric oxide synthase (NOS), we coincubated L. major promastigotes with calcimycin and selective NOS inhibitors ARL-17477 or L-NNA. Addition of these inhibitors substantially decreased the toxicity of calcimycin to Leishmania promastigotes. In doing so, we demonstrated for the first time that calcimycin has a direct leishmanicidal effect on L. major promastigotes. Also, we showed that Leishmania constitutive Ca2+/calmodulin-dependent nitric oxide synthase is involved in the parasite cell death. These data suggest activation of Leishmania nitric oxide synthase as a new therapeutic approach.
Permanent Link: http://hdl.handle.net/11104/0281159