Na(+)-ATPase and protein kinase C are targets to 1-O-hexadecylphosphocoline (miltefosine) in Trypanosoma cruzi |
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Authors: | Saraiva Victor Barbosa Wengert Mira Gomes-Quintana Elaine Heise Norton Caruso-Neves Celso |
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Affiliation: | a Laboratório de Glicobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde Bloco G, Av. Carlos Chagas Filho 373, Cidade Universitária, Ilha do Fundão, Rio de Janeiro-RJ 21941-902, Brazil b Laboratório de Bioquímica Renal, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde Bloco G, Av. Carlos Chagas Filho 373, Cidade Universitária, Ilha do Fundão, Rio de Janeiro-RJ 21941-902, Brazil |
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Abstract: | 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 IC50 = 18 ± 5 μg mL−1. This effect was shown to be reversible, dependent on the pH and Ca2+. 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. |
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Keywords: | Trypanosoma cruzi Chagas disease Na+-ATPase PKC Ether-lipid analogue Parasite growth inhibition |
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