Abstract
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.
Highlights
Curcuma longa is a plant belonging to the Zingiberacea family, which is endemic in South and Southeast of Asian Continent, being cultivated in many countries worldwide [1]
A mixture of curcuminoids present in commercially available curcumin after chromatographic separation by TLC and HPLC had each component isolated, purified and fully characterized. This mixture present in the commercial material is not resolved by thin layer chromatography (TLC) using hexanes and ethyl acetate as eluent, but it is possible to identify three spots when methanol and dichloromethane (2:98) are used
Several studies in the literature report the use of commercial curcumin in biological assessments without prior purification, so the results described in these works involve the evaluation of the three curcuminoids as a mixture (CUR, DMC and BDMC, Fig 1)
Summary
Curcuma longa is a plant belonging to the Zingiberacea family, which is endemic in South and Southeast of Asian Continent, being cultivated in many countries worldwide [1]. The main special metabolites present in C. longa belong to the sesquiterpene and diarylheptanoid classes. Curcuphenol and curlone (Fig 1) are the main sesquiterpenes in turmeric, with the concentrations of 30.0, 10.6 and 10,0% in the plant rhizomes, respectively [2]. One of the components responsible for the aroma of the C. longa essential oil, shows important biological properties such as inhibition of platelet aggregation [3] and antidiabetic [4]. Another important class of special metabolites present in C. longa are the diarylheptanoids, structurally related to curcumin (CUR), which is the most representative example of this group [5]. The α,β-unsaturated dihydropyranone moiety present in CC is formed through a Michael-type addition cyclization of curcumin
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