EVALUATION OF THE ACTION OF NEW MOLECULES ON THE REDOX SYSTEM OF Trypanosoma cruzi

GAIA A; GOMEZ J; GAURISE C; AGUILERA AC; TELLO FARAL P; ROBELLO C; CIFUENTES D; SOSA M; BARRERA P

Congreso; XXXVI Scientific Meeting of the Cuyo Biology Society; 2018

Sociedad de Biología de Cuyo

Chagas disease is caused by Trypanosoma cruzi (T. cruzi) and affects to millions of people worldwide, mostly in Latin America. Despite its sanitary importance, there are currently only two drugs available for its treatment: benznidazole and nifurtimox, both exhibiting serious adverse effects on patients. To complete its life cycle, T. cruzi undergoes drastic cellular morphological and biochemical changes as it passes from extracellular epimastigote and trypomastigote forms, to intracellular/tissue non-motile stage, as well as it faces extreme fluctuations such as oxidative environment. It is known that antioxidant defense system in the trypanosomatids is different from mammalian cells, since the parasites have exclusive molecules and reducing enzymes. Due this, parasite redox pathway is an attractive target for antiparasitic therapies. Our study is focused on the action mechanisms of the natural sesquiterpene lactones (STLs) dehydroleucodine (DhL), and here we expanded the study to derivatives: DC-X1, DC-X2, DC-X3, DC-X4, DC-X5, DC-X6 and DC-X7 obtained by chemical substitutions. We have previously described to DhL as a leishmanicida drug by oxidative stress generation. In this work, it is shown an antiproliferative effect of DhL and its chemical derivatives, being the most actives DC-X1 and DC-X3 on T. cruzi epimastigotes. This effect was blocked by 3 mM reduced glutathione, suggesting that compounds are reactive upon intracellular sulfhydryl groups. Moreover, T. cruzi overexpressing reducing enzymes, showed a protective effect against these compounds. Consistent with these results, the active STLs induced ROS generation in the wild type parasites, and this effect was at lesser extent in T. cruzi overexpressing reducing enzymes. These results indicate that the induction of oxidative stress is, at least, one of the mechanisms of STLs antiparasitic action.