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 (2mM), 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 microg 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.
Saraiva
Victor Barbosa
VB
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, Brazil.
Wengert
Mira
M
Gomes-Quintana
Elaine
E
Heise
Norton
N
Caruso-Neves
Celso
C
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D005665:Furosemide / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013552:Swine; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development
D014344:Trypanocidal Agents; D010767:Phosphorylcholine; C039128:miltefosine; D005665:Furosemide; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium