Produção Nacional
Revisado por pares
Chemotherapy
2003; UNIVERSIDADE DE SÃO PAULO; Volume: 45; Issue: suppl 13 Linguagem: Inglês
10.1590/s0036-46652003000700008
ISSN1678-9946
AutoresVíctor Barbosa Saraiva, E. Gomes-Quintana, Tienko Vitor Da Rocha, Norton Heise, Nativas De Moluscos, Bivalves Löfgren, Steindel, Barracco, Sara Emelie Löfgren, Bachère,
Tópico(s)Cancer Treatment and Pharmacology
ResumoMiltefosine, initially developed as an anti-tumor agent, is the newest drug for the treatment of visceral leishmaniasis.Several laboratories have shown that this ether-lipid analogue is also toxic against different forms of T. cruzi, but its mechanism(s) of action is(are) still unclear.In leukemic cells, Miltefosine seems to interfere with cellular signal transduction pathways by inhibition of protein kinase C (PKC) and Na + , K + -ATPase.In order to verify if Miltefosine is able to act in a similar way on T. cruzi, we initially tested its effects against on the ouabain-insensitive and furosemide-sensitive Na + -ATPase activities of the parasites (1).The Na + -ATPase activitiy was measured as described previously (1-2) using an enriched plasma membrane fraction from epimastigotes obtained after subcellular fractionation by differential centrifugation in sucrose-containing buffer.The addition of increasing amounts of Miltefosine (0,003-0,3 mg/mL) resulted in a dose-dependent inhibition of the Na + -ATPase activity.In a second stage, the inhibition of the Na + -ATPase by Miltefosine was confirmed by performing activity measurements in the presence of increasing amounts of NaCl, containing or not 0,015mg/mL of Miltefosine.As expected, there was a Na + -dependent increase of the Na + -ATPase activity, with a K 0.5 and V max of 13.7±1.9mM Na + and 11.4±0.5 nmol Pi x mg -1 x min 1 , respectively.In the presence of Miltefosine there was a change in the kinetic parameters, with the K 0.5 for Na + raising to 28.5±5.3mM and the V max dropping to 7.6±0.5 nmol Pi x mg -1 x min 1 .When the membrane fractions were pre-incubated with Miltefosine (0,015 mg/mL) and diluted to a condition containing four times less drug before performing the assay, no inhibition was observed when compared to controls.Taken together, the results suggest that Miltefosine act as a reversible inhibitor of the T. cruzi Na + -ATPase.
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