Advances in the study of anthracyclines effect on Trypanosoma cruzi

MD. RUIZ; L. FRACCAROLI; D. BALCAZAR; C. VANRELL; L. LAROCCA; P. ROMANO

Congreso; Reunión Anual de Sociedades Biocientíficas 2019; 2019

Trypanosoma cruzi (T. cruzi) is the etiological agent of Chagas disease. As current therapies are limited in efficacy, there is a need to identify new specific trypanocidal compounds.Our previous work showed that anthracyclines (antitumor agents) decreased survival and proliferation of T. cruzi epimastigotes and interfered with its putrescine uptake. The aim of this work was to deepen the study about anthracyclines effect on polyamine metabolism in epimastigotes and to analyze their effect on different T. cruzi life cycle stages.Daunorubicin (Dnr) and Doxorubicin (Dxr) were the anthracyclines selected to evaluate their effect on T. cruzi (strain Y-GFP). We performed growth curves, and measured intracellular content of polyamines, by HPLC analysis, on epimastigotes cultured in putrescine depleted medium for 1 to 15 days. Under these conditions, intracellular putrescine diminished and T. cruzi epimastigotes became significatively more sensitive to Dnr and Dxr (IC50 of 0.1μM for Dnr and 2μM for Dxr), not depending on the nutritional stress length. On the other hand, although Dxr and Dnr interfere with polyamine uptake, sub-IC50 doses of these did not change the intracellular concentration of putrescine during 15 days of culture.Anthracyclines effect was tested in in vitro metacyclogenesis, infectivity and amastigotes proliferation assays. Differentiation from epimastigotes to metacyclic trypomastigotes diminished by Dnr treatment (from 14,8% in control condition to 8,9% with Dnr). Dnr did not affect the number of infected H9C2 cells nor total number of these cells but reduced by half the number of amastigotes per cell.The findings presented herein showed that Dnr and Dxr affect T. cruzi epimastigotes survival and proliferation, metacyclogenesis and replicative capacity of amastigotes. This effect could be related to the decrease of polyamine uptake by anthracyclines and their intracellular toxic effects.