SESQUITERPENE LACTONES AFFECT THE REDOX SYSTEM OF TRYPANOSOMA CRUZI

GOMEZ J; GUARISE C; CIFUENTES D; TELLO FARAL P; ROBELLO C; SOSA MA; BARRERA P

Congreso; XXXVII Reunión Anual de la Sociedad de Biología de Cuyo; 2019

Sociedad de Biología de Cuyo

Chagas disease is caused by Trypanosoma cruzi (T. cruzi) and affects 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, bothexhibiting serious adverse effects on patients. In order to complete its life cycle, T. cruzi faces extreme environmental conditions ?i.e.oxidative stress- as it propagates from an insect vector to a mammalian host, driving the transition from non-infective epimastigote tothe infective form trypomastigote. It is known that the antioxidant defense system in the trypanosomatids is different from that inmammalian cells since the parasites have exclusive molecules and reducing enzymes. Because of this, the parasite redox machineryis an attractive target for antiparasitic therapies. The sesquiterpene lactone dehydroleucodine (DhL), is a trypanocidal molecule ?containing an alpha-methylene group that could react with sulfhydryl groups of key redox enzymes. This study was focused onelucidating the DhL mechanism of action and extended to ten DhL derivatives (DC-X1 to DC-X10) obtained by chemicalsubstitutions on the methylene group. We firstly confirmed an antiproliferative effect of DhL and its chemical derivatives, being DCX6 one of the most active. The effect of DhL and DC-X6 was blocked by reduced glutathione, suggesting that compounds arereactive to sulfhydryl groups of certain molecules. Moreover, parasites overexpressing reducing enzymes, such as Tc-CPX, showed aprotective effect against these STLs. Consistent with these results, both STLs increased ROS concentration in the wild type parasites.These results indicate that STLs induce oxidative stress on the parasites, possibly by affecting some crucial enzymes of the redoxsystem.