The Effectiveness of Natural Diarylheptanoids against Trypanosoma cruzi: Cytotoxicity, Ultrastructural Alterations and Molecular Modeling Studies.
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 cr...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5033595?pdf=render |
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| author | Vitor Sueth-Santiago Julliane de B B Moraes Eliomara Sousa Sobral Alves Marcos André Vannier-Santos Célio G Freire-de-Lima Rosane N Castro Gustavo Peron Mendes-Silva Catarina de Nigris Del Cistia Luma Godoy Magalhães Adriano Defini Andricopulo Carlos Mauricio R Sant Anna Debora Decoté-Ricardo Marco Edilson Freire de Lima |
| author_facet | Vitor Sueth-Santiago Julliane de B B Moraes Eliomara Sousa Sobral Alves Marcos André Vannier-Santos Célio G Freire-de-Lima Rosane N Castro Gustavo Peron Mendes-Silva Catarina de Nigris Del Cistia Luma Godoy Magalhães Adriano Defini Andricopulo Carlos Mauricio R Sant Anna Debora Decoté-Ricardo Marco Edilson Freire de Lima |
| author_sort | Vitor Sueth-Santiago |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T10:29:07Z |
| format | Article |
| id | doaj.art-31a4dbc55d7b4810b05eb1639ba40e60 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T10:29:07Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-31a4dbc55d7b4810b05eb1639ba40e602022-12-21T19:07:14ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01119e016292610.1371/journal.pone.0162926The Effectiveness of Natural Diarylheptanoids against Trypanosoma cruzi: Cytotoxicity, Ultrastructural Alterations and Molecular Modeling Studies.Vitor Sueth-SantiagoJulliane de B B MoraesEliomara Sousa Sobral AlvesMarcos André Vannier-SantosCélio G Freire-de-LimaRosane N CastroGustavo Peron Mendes-SilvaCatarina de Nigris Del CistiaLuma Godoy MagalhãesAdriano Defini AndricopuloCarlos Mauricio R Sant AnnaDebora Decoté-RicardoMarco Edilson Freire de LimaCurcumin (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.http://europepmc.org/articles/PMC5033595?pdf=render |
| spellingShingle | Vitor Sueth-Santiago Julliane de B B Moraes Eliomara Sousa Sobral Alves Marcos André Vannier-Santos Célio G Freire-de-Lima Rosane N Castro Gustavo Peron Mendes-Silva Catarina de Nigris Del Cistia Luma Godoy Magalhães Adriano Defini Andricopulo Carlos Mauricio R Sant Anna Debora Decoté-Ricardo Marco Edilson Freire de Lima The Effectiveness of Natural Diarylheptanoids against Trypanosoma cruzi: Cytotoxicity, Ultrastructural Alterations and Molecular Modeling Studies. PLoS ONE |
| title | The Effectiveness of Natural Diarylheptanoids against Trypanosoma cruzi: Cytotoxicity, Ultrastructural Alterations and Molecular Modeling Studies. |
| title_full | The Effectiveness of Natural Diarylheptanoids against Trypanosoma cruzi: Cytotoxicity, Ultrastructural Alterations and Molecular Modeling Studies. |
| title_fullStr | The Effectiveness of Natural Diarylheptanoids against Trypanosoma cruzi: Cytotoxicity, Ultrastructural Alterations and Molecular Modeling Studies. |
| title_full_unstemmed | The Effectiveness of Natural Diarylheptanoids against Trypanosoma cruzi: Cytotoxicity, Ultrastructural Alterations and Molecular Modeling Studies. |
| title_short | The Effectiveness of Natural Diarylheptanoids against Trypanosoma cruzi: Cytotoxicity, Ultrastructural Alterations and Molecular Modeling Studies. |
| title_sort | effectiveness of natural diarylheptanoids against trypanosoma cruzi cytotoxicity ultrastructural alterations and molecular modeling studies |
| url | http://europepmc.org/articles/PMC5033595?pdf=render |
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