21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions.
Cardiotonic steroids are used to treat heart failure and arrhythmia and have promising anticancer effects. The prototypic cardiotonic steroid ouabain may also be a hormone that modulates epithelial cell adhesion. Cardiotonic steroids consist of a steroid nucleus and a lactone ring, and their biologi...
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2014
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oai:doaj.org-article:be6b9f94d29e4b688e9429a2fc67ac6a2021-11-25T05:57:41Z21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions.1932-620310.1371/journal.pone.0108776https://doaj.org/article/be6b9f94d29e4b688e9429a2fc67ac6a2014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0108776https://doaj.org/toc/1932-6203Cardiotonic steroids are used to treat heart failure and arrhythmia and have promising anticancer effects. The prototypic cardiotonic steroid ouabain may also be a hormone that modulates epithelial cell adhesion. Cardiotonic steroids consist of a steroid nucleus and a lactone ring, and their biological effects depend on the binding to their receptor, Na,K-ATPase, through which, they inhibit Na+ and K+ ion transport and activate of several intracellular signaling pathways. In this study, we added a styrene group to the lactone ring of the cardiotonic steroid digoxin, to obtain 21-benzylidene digoxin (21-BD), and investigated the effects of this synthetic cardiotonic steroid in different cell models. Molecular modeling indicates that 21-BD binds to its target Na,K-ATPase with low affinity, adopting a different pharmacophoric conformation when bound to its receptor than digoxin. Accordingly, 21-DB, at relatively high µM amounts inhibits the activity of Na,K-ATPase α1, but not α2 and α3 isoforms. In addition, 21-BD targets other proteins outside the Na,K-ATPase, inhibiting the multidrug exporter Pdr5p. When used on whole cells at low µM concentrations, 21-BD produces several effects, including: 1) up-regulation of Na,K-ATPase expression and activity in HeLa and RKO cancer cells, which is not found for digoxin, 2) cell specific changes in cell viability, reducing it in HeLa and RKO cancer cells, but increasing it in normal epithelial MDCK cells, which is different from the response to digoxin, and 3) changes in cell-cell interaction, altering the molecular composition of tight junctions and elevating transepithelial electrical resistance of MDCK monolayers, an effect previously found for ouabain. These results indicate that modification of the lactone ring of digoxin provides new properties to the compound, and shows that the structural change introduced could be used for the design of cardiotonic steroid with novel functions.Sayonarah C RochaMarco T C PessoaLuiza D R NevesSilmara L G AlvesLuciana M SilvaHerica L SantosSoraya M F OliveiraAlex G TarantoMoacyr ComarIsabella V GomesFabio V SantosNatasha PaixãoLuis E M QuintasFrançois NoëlAntonio F PereiraAna C S C TessisNatalia L S GomesOtacilio C MoreiraRuth Rincon-HerediaFernando P VarottiGustavo BlancoJose A F P VillarRubén G ContrerasLeandro A BarbosaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 10, p e108776 (2014) |
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Medicine R Science Q Sayonarah C Rocha Marco T C Pessoa Luiza D R Neves Silmara L G Alves Luciana M Silva Herica L Santos Soraya M F Oliveira Alex G Taranto Moacyr Comar Isabella V Gomes Fabio V Santos Natasha Paixão Luis E M Quintas François Noël Antonio F Pereira Ana C S C Tessis Natalia L S Gomes Otacilio C Moreira Ruth Rincon-Heredia Fernando P Varotti Gustavo Blanco Jose A F P Villar Rubén G Contreras Leandro A Barbosa 21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions. |
| description |
Cardiotonic steroids are used to treat heart failure and arrhythmia and have promising anticancer effects. The prototypic cardiotonic steroid ouabain may also be a hormone that modulates epithelial cell adhesion. Cardiotonic steroids consist of a steroid nucleus and a lactone ring, and their biological effects depend on the binding to their receptor, Na,K-ATPase, through which, they inhibit Na+ and K+ ion transport and activate of several intracellular signaling pathways. In this study, we added a styrene group to the lactone ring of the cardiotonic steroid digoxin, to obtain 21-benzylidene digoxin (21-BD), and investigated the effects of this synthetic cardiotonic steroid in different cell models. Molecular modeling indicates that 21-BD binds to its target Na,K-ATPase with low affinity, adopting a different pharmacophoric conformation when bound to its receptor than digoxin. Accordingly, 21-DB, at relatively high µM amounts inhibits the activity of Na,K-ATPase α1, but not α2 and α3 isoforms. In addition, 21-BD targets other proteins outside the Na,K-ATPase, inhibiting the multidrug exporter Pdr5p. When used on whole cells at low µM concentrations, 21-BD produces several effects, including: 1) up-regulation of Na,K-ATPase expression and activity in HeLa and RKO cancer cells, which is not found for digoxin, 2) cell specific changes in cell viability, reducing it in HeLa and RKO cancer cells, but increasing it in normal epithelial MDCK cells, which is different from the response to digoxin, and 3) changes in cell-cell interaction, altering the molecular composition of tight junctions and elevating transepithelial electrical resistance of MDCK monolayers, an effect previously found for ouabain. These results indicate that modification of the lactone ring of digoxin provides new properties to the compound, and shows that the structural change introduced could be used for the design of cardiotonic steroid with novel functions. |
| format |
article |
| author |
Sayonarah C Rocha Marco T C Pessoa Luiza D R Neves Silmara L G Alves Luciana M Silva Herica L Santos Soraya M F Oliveira Alex G Taranto Moacyr Comar Isabella V Gomes Fabio V Santos Natasha Paixão Luis E M Quintas François Noël Antonio F Pereira Ana C S C Tessis Natalia L S Gomes Otacilio C Moreira Ruth Rincon-Heredia Fernando P Varotti Gustavo Blanco Jose A F P Villar Rubén G Contreras Leandro A Barbosa |
| author_facet |
Sayonarah C Rocha Marco T C Pessoa Luiza D R Neves Silmara L G Alves Luciana M Silva Herica L Santos Soraya M F Oliveira Alex G Taranto Moacyr Comar Isabella V Gomes Fabio V Santos Natasha Paixão Luis E M Quintas François Noël Antonio F Pereira Ana C S C Tessis Natalia L S Gomes Otacilio C Moreira Ruth Rincon-Heredia Fernando P Varotti Gustavo Blanco Jose A F P Villar Rubén G Contreras Leandro A Barbosa |
| author_sort |
Sayonarah C Rocha |
| title |
21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions. |
| title_short |
21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions. |
| title_full |
21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions. |
| title_fullStr |
21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions. |
| title_full_unstemmed |
21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions. |
| title_sort |
21-benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates na,k-atpase and epithelial tight junctions. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/be6b9f94d29e4b688e9429a2fc67ac6a |
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