Na +-ATPase and protein kinase C are targets to 1- O-hexadecylphosphocoline (miltefosine) in Trypanosoma cruzi

Miltefosine has been shown to be a very active compound against Trypanosoma cruzi. Here, we evaluated the effects of miltefosine on the activity of the Na +-ATPase and protein kinase C (PKC) present in the plasma membrane of T. cruzi. Furosemide (2 mM), a specific inhibitor of Na +-ATPase, abolished...

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Bibliographic Details
Published in:Archives of biochemistry and biophysics 2009, Vol.481 (1), p.65-71
Main Authors: Saraiva, Victor Barbosa, Wengert, Mira, Gomes-Quintana, Elaine, Heise, Norton, Caruso-Neves, Celso
Format: Article
Language:English
Subjects:
Animals
Calcium - metabolism
Cell Membrane - enzymology
Chagas disease
Ether–lipid analogue
Furosemide - pharmacology
Hydrogen-Ion Concentration
Kinetics
Na +-ATPase
Parasite growth inhibition
Phosphorylcholine - analogs & derivatives
Phosphorylcholine - pharmacology
PKC
Protein Kinase C - antagonists & inhibitors
Protein Kinase C - metabolism
Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors
Sodium-Potassium-Exchanging ATPase - metabolism
Swine
Trypanocidal Agents - pharmacology
Trypanosoma cruzi
Trypanosoma cruzi - drug effects
Trypanosoma cruzi - enzymology
Trypanosoma cruzi - growth & development
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Summary:Miltefosine has been shown to be a very active compound against Trypanosoma cruzi. Here, we evaluated the effects of miltefosine on the activity of the Na +-ATPase and protein kinase C (PKC) present in the plasma membrane of T. cruzi. Furosemide (2 mM), a specific inhibitor of Na +-ATPase, abolished the growth of T. cruzi showing a crucial role of this enzyme to parasite growth. Miltefosine inhibited the Na +-ATPase activity with IC 50 = 18 ± 5 μg mL −1. This effect was shown to be reversible, dependent on the pH and Ca 2+. The inhibition was not observed when the membranes were solubilized with 0.1% deoxycholate, suggesting that the interaction between the enzyme and membrane phospholipids might be important for the drug effect. Miltefosine also inhibited the parasite PKC activity, but through a Na +-ATPase-independent way. Altogether the results indicate that miltefosine inhibits T. cruzi growth through, at least in part, the inhibition of both Na +-ATPase and PKC activities.
ISSN:0003-9861
1096-0384
DOI:10.1016/j.abb.2008.10.018