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21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions

Rocha, Sayonarah C ; Pessoa, Marco T C ; Neves, Luiza D R ; Alves, Silmara L G ; Silva, Luciana M ; Santos, Herica L ; Oliveira, Soraya M F ; Taranto, Alex G ; Comar, Moacyr ; Gomes, Isabella V ; Santos, Fabio V ; Paixão, Natasha ; Quintas, Luis E M ; Noël, François ; Pereira, Antonio F ; Tessis, Ana C S C ; Gomes, Natalia L S ; Moreira, Otacilio C ; Rincon-Heredia, Ruth ; Varotti, Fernando P ; Blanco, Gustavo ; Villar, Jose A F P ; Contreras, Rubén G ; Barbosa, Leandro A Singh, Shree Ram

PloS one, 2014-10, Vol.9 (10), p.e108776 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions
Autor: Rocha, Sayonarah C ; Pessoa, Marco T C ; Neves, Luiza D R ; Alves, Silmara L G ; Silva, Luciana M ; Santos, Herica L ; Oliveira, Soraya M F ; Taranto, Alex G ; Comar, Moacyr ; Gomes, Isabella V ; Santos, Fabio V ; Paixão, Natasha ; Quintas, Luis E M ; Noël, François ; Pereira, Antonio F ; Tessis, Ana C S C ; Gomes, Natalia L S ; Moreira, Otacilio C ; Rincon-Heredia, Ruth ; Varotti, Fernando P ; Blanco, Gustavo ; Villar, Jose A F P ; Contreras, Rubén G ; Barbosa, Leandro A
Singh, Shree Ram
Assuntos: Adenosine triphosphatase ; Analysis ; Animals ; Anticancer properties ; Apoptosis ; Apoptosis - drug effects ; Arrhythmia ; ATPases ; Biological effects ; Biology and Life Sciences ; Biophysics ; Cancer ; Cancer cells ; Caprolactone ; Cardenolides - metabolism ; Cardenolides - pharmacology ; Cell adhesion ; Cell culture ; Cell growth ; Cell Line, Tumor ; Conformation ; Digoxin ; Digoxin - analogs & derivatives ; Digoxin - chemistry ; Digoxin - pharmacology ; Electrical junctions ; Enzyme Activation - drug effects ; Epithelial cells ; Epithelial Cells - drug effects ; Epithelial Cells - metabolism ; Heart ; Heart diseases ; Humans ; Intracellular signalling ; Ion transport ; Isoforms ; Kidneys ; Medicine and Health Sciences ; Metastasis ; Mice ; Models, Molecular ; Molecular Conformation ; Molecular modelling ; Na+/K+-exchanging ATPase ; Neoplasms - genetics ; Neoplasms - metabolism ; Neurosciences ; Nuclei ; Nuclei (cytology) ; Ouabain ; Pharmacology ; Physiology ; Proteins ; Rats ; Sodium-Potassium-Exchanging ATPase - chemistry ; Sodium-Potassium-Exchanging ATPase - genetics ; Sodium-Potassium-Exchanging ATPase - metabolism ; Steroid hormones ; Steroids ; Styrene ; Tight junctions ; Tight Junctions - drug effects
É parte de: PloS one, 2014-10, Vol.9 (10), p.e108776
Notas: Conceived and designed the experiments: FPV LMS AGT MC HLS FVS LEQ FGN AFP OCM GB JAFPV RGC LAB. Performed the experiments: SCR MTCP LDRN SLGA SMFO IVG ACSCT NLSG RRH NP. Analyzed the data: FPV LMS AGT MC FVS LEQ FGN AFP OCM GB JAFPV RGC LAB. Contributed reagents/materials/analysis tools: FPV LMS AGT MC HLS FVS LEQ FGN AFP OCM GB JAFPV RGC LAB. Contributed to the writing of the manuscript: FPV LMS AGT MC FVS LEQ FGN AFP OCM GB JAFPV RGC LAB.
Competing Interests: The authors have declared that no competing interests exist.
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions

United States: Public Library of Science

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