SESQUITERPENE LACTONES INDUCE OXIDATIVE STRESS ON Trypanosoma cruzi

CIFUENTE DA; SPINA RM; SOSA MA; TELLO FARAL P; BARRERA P; ROBELLO C; GAIA A

San Luis

Congreso; XXXV Reunión Científica Anual de la Sociedad de Biología de Cuyo; 2017

Sociedad Biología de Cuyo

Chagas disease is a parasitic infection caused by the protozoan Trypanosoma cruzi (T. cruzi) that affects about 6 million people 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 should alternate between mammalian and invertebrate hosts, and face 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 research is focused on the action mechanisms of the natural sesquiterpene lactones (STLs) dehydroleucodine (DhL) and some derivatives such as DC-X-1, DC-X-2, DC-X3 and DC-X4 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 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.