Um serviço digital da FCT Publicação
The fungal metabolite eurochevalierine, a sequiterpene alkaloid, displays anti-cancer properties through selective sirtuin 1/2 inhibition
| Resumo: | NAD+-dependent histone deacetylases (sirtuins) are implicated in cellular processes such as proliferation, DNA repair, and apoptosis by regulating gene expression and the functions of numerous proteins. Due to their key role in cells, the discovery of small molecule sirtuin modulators has been of significant interest for diverse therapeutic applications. In particular, it has been shown that inhibition of sirtuin 1 and 2 activities is beneficial for cancer treatment. Here, we demonstrate that the fungal metabolite eurochevalierine from the fungus Neosartorya pseudofischeri inhibits sirtuin 1 and 2 activities (IC50 about 10 µM) without affecting sirtuin 3 activity. The binding modes of the eurochevalierine for sirtuin 1 and 2 have been identified through computational docking analyses. Accordingly, this sequiterpene alkaloid induces histone H4 and α-tubulin acetylation in various cancer cell models in which it induces strong cytostatic effects without affecting significantly the viability of healthy PBMCs. Importantly, eurochevalierine targets preferentially cancer cell proliferation (selectivity factor 7), as normal human primary CD34+ stem/progenitor cells were less affected by the treatment. Finally, eurochevalierine displays suitable drug-likeness parameters and therefore represent a promising scaffold for lead molecule optimization to study the mechanism and biological roles of sirtuins and potentially a basis for development into therapeutics. © 2018 by the authors. |
|---|---|
| Assunto: | Histones SIRT2 protein, human alkaloid protein domain Acetylation binding site SIRT3 protein, human Binding Sites beta sheet Tubulin metabolism acetylation gene expression regulation protein processing Protein Processing, Post-Translational histone molecular docking Gene Expression Regulation, Neoplastic Humans Molecular Docking Simulation Protein Interaction Domains and Motifs human protein binding sesquiterpene histone deacetylase inhibitor genetics Protein Conformation, alpha-Helical chemistry Sesquiterpenes Antineoplastic Agents Sirtuin 3 Alkaloids isolation and purification Sirtuin 2 Protein Conformation, beta-Strand antineoplastic agent Sirtuin 1 Histone Deacetylase Inhibitors tubulin antagonists and inhibitors SIRT1 protein, human Neosartorya sirtuin 1 sirtuin 2 sirtuin 3 Protein Binding alpha helix |
| País: | Portugal |
| Tipo de documento: | journal article |
| Tipo de acesso: | Aberto |
| Instituição associada: | Repositório Aberto da Universidade do Porto |
| Idioma: | inglês |
| Origem: | Repositório Aberto da Universidade do Porto |
| _version_ | 1850560650246356992 |
|---|---|
| conditionsOfAccess_str | open access |
| country_str | PT |
| description | NAD+-dependent histone deacetylases (sirtuins) are implicated in cellular processes such as proliferation, DNA repair, and apoptosis by regulating gene expression and the functions of numerous proteins. Due to their key role in cells, the discovery of small molecule sirtuin modulators has been of significant interest for diverse therapeutic applications. In particular, it has been shown that inhibition of sirtuin 1 and 2 activities is beneficial for cancer treatment. Here, we demonstrate that the fungal metabolite eurochevalierine from the fungus Neosartorya pseudofischeri inhibits sirtuin 1 and 2 activities (IC50 about 10 µM) without affecting sirtuin 3 activity. The binding modes of the eurochevalierine for sirtuin 1 and 2 have been identified through computational docking analyses. Accordingly, this sequiterpene alkaloid induces histone H4 and α-tubulin acetylation in various cancer cell models in which it induces strong cytostatic effects without affecting significantly the viability of healthy PBMCs. Importantly, eurochevalierine targets preferentially cancer cell proliferation (selectivity factor 7), as normal human primary CD34+ stem/progenitor cells were less affected by the treatment. Finally, eurochevalierine displays suitable drug-likeness parameters and therefore represent a promising scaffold for lead molecule optimization to study the mechanism and biological roles of sirtuins and potentially a basis for development into therapeutics. © 2018 by the authors. |
| documentTypeURL_str | http://purl.org/coar/resource_type/c_6501 |
| documentType_str | journal article |
| id | 5b657eed-3990-4c36-8501-22a97619e773 |
| identifierHandle_str | https://hdl.handle.net/10216/120520 |
| language | eng |
| relatedInstitutions_str_mv | Repositório Aberto da Universidade do Porto |
| resourceName_str | Repositório Aberto da Universidade do Porto |
| spellingShingle | The fungal metabolite eurochevalierine, a sequiterpene alkaloid, displays anti-cancer properties through selective sirtuin 1/2 inhibition Histones SIRT2 protein, human alkaloid protein domain Acetylation binding site SIRT3 protein, human Binding Sites beta sheet Tubulin metabolism acetylation gene expression regulation protein processing Protein Processing, Post-Translational histone molecular docking Gene Expression Regulation, Neoplastic Humans Molecular Docking Simulation Protein Interaction Domains and Motifs human protein binding sesquiterpene histone deacetylase inhibitor genetics Protein Conformation, alpha-Helical chemistry Sesquiterpenes Antineoplastic Agents Sirtuin 3 Alkaloids isolation and purification Sirtuin 2 Protein Conformation, beta-Strand antineoplastic agent Sirtuin 1 Histone Deacetylase Inhibitors tubulin antagonists and inhibitors SIRT1 protein, human Neosartorya sirtuin 1 sirtuin 2 sirtuin 3 Protein Binding alpha helix |
| title | The fungal metabolite eurochevalierine, a sequiterpene alkaloid, displays anti-cancer properties through selective sirtuin 1/2 inhibition |
| topic | Histones SIRT2 protein, human alkaloid protein domain Acetylation binding site SIRT3 protein, human Binding Sites beta sheet Tubulin metabolism acetylation gene expression regulation protein processing Protein Processing, Post-Translational histone molecular docking Gene Expression Regulation, Neoplastic Humans Molecular Docking Simulation Protein Interaction Domains and Motifs human protein binding sesquiterpene histone deacetylase inhibitor genetics Protein Conformation, alpha-Helical chemistry Sesquiterpenes Antineoplastic Agents Sirtuin 3 Alkaloids isolation and purification Sirtuin 2 Protein Conformation, beta-Strand antineoplastic agent Sirtuin 1 Histone Deacetylase Inhibitors tubulin antagonists and inhibitors SIRT1 protein, human Neosartorya sirtuin 1 sirtuin 2 sirtuin 3 Protein Binding alpha helix |