DEHYDROLEUCODINE AND SOME CHEMICAL DERIVATES AFFECT PROLIFERATION OF Trypanosoma cruzi BY ALTERING DIFFERENT MOLECULAR TARGETS

GOMEZ J; GUARISE C; GAIA A; PATRICIA CABALLERO; CIFUENTES D; MIGUEL A. SOSA; BARRERA P

Congreso; IV JOINT MEETING OF THE BIOLOGY SOCIETIES OF ARGENTINA; 2020

Sociedad de Biología de Cuyo

Chagas disease is endemic in Latin America and affects to millions of people worldwide. This pathology is caused by the trypanosomatidTrypanosoma cruzi (T. cruzi). The current chemotherapy is based on the nitroderivatives Benznidazole and Nifurtimox, but their use is restricted dueto the severe side effects on the patients, justifying the continuous search for alternative drugs. The antioxidant defense system of thetrypanosomatids is different from that of mammalian cells, having a particular set of reducing molecules and enzymes. Hence, the redox system ofthe parasite emerges as an attractive target for new antiparasitic therapies. The natural sesquiterpene lactone dehydroleucodine (DhL) is known tohave an important antiparasitic activity. The α-methylene group of DhL could be responsible of its biological activities, possibly by blocking thethiols groups present in reducing molecules or enzymes. In this study we attempted to elucidate the mechanism of action of DhL and elevenderivatives (named DC-X1 to DC-X11) obtained by chemical substitutions on the methylene group. We confirmed the antiproliferative effect of thisnatural compounds, being the most active DhL, DC-X3, DC-X6 and DC-X11. Based on the background of DhL, we focused the study on the parasiteantioxidative machinery. Thereby, T. cruzi epimastigotes were incubated with DhL and DC-X6 and intracellular ROS generation was evaluated. Asignificant increase of ROS was induced by DhL and at lesser extent by DC-X6. This effect was blocked by adding reduced glutathione. Theseresults suggest that DhL and DC-X6 can induce oxidative stress in the parasites by inactivation of reducing enzymes, or by capture of reducingmolecules (trypanotion or glutathione), affecting their redox homeostasis. On the other hand, we observed that DC-X11 alters the cell cycle ofparasites synchronized with hydroxyurea (20 mM), which could lead to the apoptosis. Through the use of chemical derivatives, we confirmed theimportance of the methylene group in the mechanism of action of DhL. Our study provides new insights about the possible targets for a potentialdrug against Chagas.