Putrescine analogue cytotoxicity against Trypanosoma cruzi

Abstract

Trypanosoma cruzi is the etiological agent of American trypanosomiasis. Most of the available data on trypanosomatid parasites were obtained from African trypanosomes. Parasitic protozoa polyamine metabolism and transport pathways comprise valuable targets for chemotherapy. T. cruzi cannot synthesize putrescine, but its uptake from the extracellular milieu can promote parasite survival. Nevertheless, little is known about the cell biology of this diamine in T. cruzi. Here we notice that the putrescine analogue 1,4-diamino-2-butanone (DAB) inhibited T. cruzi epimastigotes' in vitro proliferation and produced remarkable mitochondrial destruction and cell architecture disorganization, as assessed by transmission electron microscopy. Mitochondrial damage was confirmed by MTT reduction. We decided to analyze the oxidative stress undergone by DAB-treated parasites. Thiobarbituric-acid-reactive substances were measured to assess lipid peroxidation. Analogue effects were dose-dependent; 5 mM DAB only slightly enhanced peroxidation, whereas 10 mM DAB significantly (P < 0.05) diminished it. These data indicate that putrescine uptake by this diamine auxotrophic parasite may be important for epimastigote axenic growth and cellular organization.

The putrescine analogue 1,4-diamino-2-butanone affects polyamine synthesis, transport, ultrastructure and intracellular survival in Leishmania amazonensis

“…Magnification: A and D, ¾75 000; B ¾40 000; C ¾87 000; E, ¾33 500; F, ¾71 000. The antiproliferative effect of DAB may be due, at least in part, to destruction of mitochondria as reported for spermine analogues (Stevens et al, 1977), consistent with the observed reduction in O 2 consumption in DFMOtreated Trypanosoma brucei (McCann et al, 1981) and with gross mitochondrial ultrastructural alterations in DABtreated T. cruzi (Menezes et al, 2006). We have previously shown that DAB leads to the destruction of the trichomonad redox organelle (Reis et al, 1999), suggesting a conserved mode of action of DAB in unrelated parasitic protozoa.…”

“…The putrescine analogue DAB has been tested in different micro-organisms (Calvo-Méndez et al, 1993;ArteagaNieto et al, 1996;Reis et al, 1999;Garcia et al, 2005;Menezes et al, 2006) and was effective against DFMOresistant parasites (Calvo-Méndez et al, 1993;Reis et al, 1999). DAB has also been shown to be a powerful ODC inhibitor in a number of organisms (Calvo-Méndez et al, 1993;Arteaga-Nieto et al, 1996).…”

“…The bis(benzyl)polyamine analogues also show significant activity against Leishmania donovani amastigotes in vitro and in vivo (Baumann et al, 1990). We have previously shown that the putrescine analogue 1,4-diamino-2-butanone (DAB) blocks the proliferation of Tritrichononas foetus (Reis et al, 1999) and Trypanosoma cruzi (Menezes et al, 2006). Here we tested the effects of DAB on Leishmania amazonensis proliferation, putrescine uptake and biosynthesis, ultrastructure and macrophage infection.…”

Effects of a putrescine analog on Giardia lamblia

“…We have previously noticed that DAB inhibits the growth of anaerobic trichomonad parasite Tritrichomonas foetus (Reis et al 1999) and T. cruzi (Menezes et al 2006), but little is known about the role of putrescine in Giardia cell biology. Here, we examined the effects of DAB in G. lamblia trophozoite proliferation, differentiation, ultrastructure, and oxidative stress.…”

Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

“…However, it was not effective against Leishmania or T. cruzi due to differences in the gene and an inability to produce significant amounts of putrescine, respectively [60][61][62][63]. Use of the putrescine analogue 1,4-diamino-2-butanone (DAB) caused inhibition of the proliferation of Leishmania and T. cruzi and severe damage to the mitochondrion characterized by swelling, fenestration and the presence of few cristae [64][65][66][67][68].…”