The Effectiveness of Natural Diarylheptanoids against Trypanosoma cruzi: Cytotoxicity, Ultrastructural Alterations and Molecular Modeling Studies

• Published in: PloS one Vol. 11; no. 9; p. e0162926
• Main Authors: Sueth-Santiago, Vitor, Moraes, Julliane de B B, Sobral Alves, Eliomara Sousa, Vannier-Santos, Marcos André, Freire-de-Lima, Célio G, Castro, Rosane N, Mendes-Silva, Gustavo Peron, Del Cistia, Catarina de Nigris, Magalhães, Luma Godoy, Andricopulo, Adriano Defini, Sant Anna, Carlos Mauricio R, Decoté-Ricardo, Debora, Freire de Lima, Marco Edilson
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2016; Public Library of Science (PLoS)
• Subjects: Active control; Alterations; Apoptosis; Binding sites; Biology and Life Sciences; Curcuma longa; Curcumin; Cytometry; Cytoskeleton; Cytotoxicity; Deoxyribonucleic acid; DNA; Electron microscopy; Epimastigotes; Flow cytometry; Homology; Hydrogen; Hydrogen bonds; Leishmania; Macrophages; Medicine and Health Sciences; Metabolites; Microtubules; Mode of action; Molecular chains; Molecular docking; Molecular modelling; Paclitaxel; Parasites; Parasitic diseases; Peritoneum; Plasmodium falciparum; Properties (attributes); Proteins; Protozoa; R&D; Research & development; Rhizomes; Toxicity; Tropical diseases; Trypanosoma brucei; Trypanosoma cruzi; Trypomastigotes; Tubulin; Brazil; Rio de Janeiro Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0162926

Curcumin (CUR) is the major constituent of the rhizomes of Curcuma longa and has been widely investigated for its chemotherapeutic properties. The well-known activity of CUR against Leishmania sp., Trypanosoma brucei and Plasmodium falciparum led us to investigate its activity against Trypanosoma cruzi. In this work, we tested the cytotoxic effects of CUR and other natural curcuminoids on different forms of T. cruzi, as well as the ultrastructural changes induced in epimastigote form of the parasite. CUR was verified as the curcuminoid with more significant trypanocidal properties (IC50 10.13 μM on epimastigotes). Demethoxycurcumin (DMC) was equipotent to CUR (IC50 11.07 μM), but bisdemethoxycurcumin (BDMC) was less active (IC50 45.33 μM) and cyclocurcumin (CC) was inactive. In the experiment with infected murine peritoneal macrophages all diarylheptanoids were more active than the control in the inhibition of the trypomastigotes release. The electron microscopy images showed ultrastructural changes associated with the cytoskeleton of the parasite, indicating tubulin as possible target of CUR in T. cruzi. The results obtained by flow cytometry analysis of DNA content of the parasites treated with natural curcuminoids suggested a mechanism of action on microtubules related to the paclitaxel`s mode of action. To better understand the mechanism of action highlighted by electron microscopy and flow cytometry experiments we performed the molecular docking of natural curcuminoids on tubulin of T. cruzi in a homology model and the results obtained showed that the observed interactions are in accordance with the IC50 values found, since there CUR and DMC perform similar interactions at the binding site on tubulin while BDMC do not realize a hydrogen bond with Lys163 residue due to the absence of methoxyl groups. These results indicate that trypanocidal properties of CUR may be related to the cytoskeletal alterations.