21-Benzylidene Digoxin: A Proapoptotic Cardenolide of Cancer Cells That Up-Regulates Na,K-ATPase and Epithelial Tight Junctions
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2014 |
| Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/10192 |
Resumo: | Universidade Federal de São João del Rei. Laboratório de Bioquimica Celular. Campus Centro-Oeste Dona Lindú, Divinópolis, MG, Brasil. |
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Rocha, Sayonarah C.Pessoa, Marco T. C.Neves, Luiza D. R.Alves, Silmara L. G.Silva, Luciana M.Santos, Hérica L.Oliveira, Soraya M. F.Taranto, Alex G.Comar, MoacyrGomes, Isabella V.Santos, Fabio V.Paixão, NatashaQuintas, Luis E. M.Nöel, FrançoisPereira, Antonio F.Tessis, Ana C. S. C.Gomes, Natalia L. S.Moreira, Otacilio C.Rincon-Heredia, RuthVarotti, Fernando P.Blanco, GustavoVillar, Jose A. F. P.Contreras, Rubén G.Barbosa, Leandro A.2015-05-04T17:07:27Z2015-05-04T17:07:27Z2014ROCHA, Sayonarah C. et al. 21-Benzylidene Digoxin: A Proapoptotic Cardenolide of Cancer Cells That Up-Regulates Na,K-ATPase and Epithelial Tight Junctions. Plos One, v.9, n.10, 14p, 2014.https://www.arca.fiocruz.br/handle/icict/1019210.1371/journal.pone.0108776engPlos One21-Benzylidene Digoxin: A Proapoptotic Cardenolide of Cancer Cells That Up-Regulates Na,K-ATPase and Epithelial Tight Junctionsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleUniversidade Federal de São João del Rei. Laboratório de Bioquimica Celular. Campus Centro-Oeste Dona Lindú, Divinópolis, MG, Brasil.Universidade Federal de São João del Rei. Laboratório de Bioquimica Celular. Campus Centro-Oeste Dona Lindú, Divinópolis, MG, Brasil.Universidade Federal de São João del Rei. Laboratório de Bioquimica Celular. Campus Centro-Oeste Dona Lindú, Divinópolis, MG, Brasil.Universidade Federal de São João del Rei. Laboratório de Síntese Orgânica. Campus Centro-Oeste Dona Lindú, Divinópolis, MG, Brasil.Fundação Ezequiel Dias. Laboratório de Biologia Celular e Inovação Biotecnológica. Belo Horizonte, MG, BrasilUniversidade Federal de São João del Rei. Laboratório de Bioquimica Celular. Campus Centro-Oeste Dona Lindú, Divinópolis, MG, Brasil.Universidade Federal de São João del Rei. Laboratório de Bioinformática. Campus Centro-Oeste Dona Lindú. São João del Rei, MG, Brasil.Universidade Federal de São João del Rei. Laboratório de Bioinformática. Campus Centro-Oeste Dona Lindú. São João del Rei, MG, Brasil.Universidade Federal de São João del Rei. Laboratório de Bioinformática. Campus Centro-Oeste Dona Lindú. São João del Rei, MG, Brasil.Universidade Federal de São João del Rei. Laboratório de Biologia Celular e Mutagenicidade. Campus Centro-Oeste Dona Lindú, Divinópolis, MG, Brasil.Universidade Federal de São João del Rei. Laboratório de Biologia Celular e Mutagenicidade. Campus Centro-Oeste Dona Lindú, Divinópolis, MG, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Laboratório de Farmacologia Bioquímica e Molecular. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Laboratório de Farmacologia Bioquímica e Molecular. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Laboratório de Farmacologia Bioquímica e Molecular. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo Góes. Laboratório de Bioquímica Microbiana. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo Góes. Laboratório de Bioquímica Microbiana. Rio de Janeiro, RJ, Brasil / Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ), Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil.Center for Research and Advanced Studies (Cinvestav). Department of Physiology, Biophysics and Neurosciences. Mexico City, Mexico.Universidade Federal de São João del Rei. Laboratório de Bioquímica de Parasitos. Campus Centro-Oeste Dona Lindú. Divinópolis, MG, BrasilUniversity of Kansas Medical Center.Department of Molecular and Integrative Physiology. Kansas City, Kansas, USA.Universidade Federal de São João del Rei. Laboratório de Síntese Orgânica. Campus Centro-Oeste Dona Lindú, Divinópolis, MG, BrasilCenter for Research and Advanced Studies (Cinvestav). Department of Physiology, Biophysics and Neurosciences. Mexico City, Mexico.Universidade Federal de São João del Rei. Laboratório de Bioquimica Celular. Campus Centro-Oeste Dona Lindú, Divinópolis, MG, Brasil.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.Benzylidene digoxinCancer cellsCardiotonic steroidsGlicósidos CardíacosGlicosídeos Cardíacosinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txttext/plain1914https://www.arca.fiocruz.br/bitstream/icict/10192/1/license.txt7d48279ffeed55da8dfe2f8e81f3b81fMD51ORIGINALotacilio_moreiraetal_IOC_2014.pdfapplication/pdf1002139https://www.arca.fiocruz.br/bitstream/icict/10192/2/otacilio_moreiraetal_IOC_2014.pdf080fda54ccd9c507f627e8ec87824969MD52TEXTotacilio_moreiraetal_IOC_2014.pdf.txtotacilio_moreiraetal_IOC_2014.pdf.txtExtracted texttext/plain82043https://www.arca.fiocruz.br/bitstream/icict/10192/3/otacilio_moreiraetal_IOC_2014.pdf.txt40d1a8681c1cf2d6b129cf65f8e661beMD53icict/101922022-06-24 13:10:45.043oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352022-06-24T16:10:45Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false |
| dc.title.pt_BR.fl_str_mv |
21-Benzylidene Digoxin: A Proapoptotic Cardenolide of Cancer Cells That Up-Regulates Na,K-ATPase and Epithelial Tight Junctions |
| title |
21-Benzylidene Digoxin: A Proapoptotic Cardenolide of Cancer Cells That Up-Regulates Na,K-ATPase and Epithelial Tight Junctions |
| spellingShingle |
21-Benzylidene Digoxin: A Proapoptotic Cardenolide of Cancer Cells That Up-Regulates Na,K-ATPase and Epithelial Tight Junctions Rocha, Sayonarah C. Benzylidene digoxin Cancer cells Cardiotonic steroids Glicósidos Cardíacos Glicosídeos Cardíacos |
| 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 |
| author |
Rocha, Sayonarah C. |
| author_facet |
Rocha, Sayonarah C. Pessoa, Marco T. C. Neves, Luiza D. R. Alves, Silmara L. G. Silva, Luciana M. Santos, Hérica L. Oliveira, Soraya M. F. Taranto, Alex G. Comar, Moacyr Gomes, Isabella V. Santos, Fabio V. Paixão, Natasha Quintas, Luis E. M. Nöel, 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. |
| author_role |
author |
| author2 |
Pessoa, Marco T. C. Neves, Luiza D. R. Alves, Silmara L. G. Silva, Luciana M. Santos, Hérica L. Oliveira, Soraya M. F. Taranto, Alex G. Comar, Moacyr Gomes, Isabella V. Santos, Fabio V. Paixão, Natasha Quintas, Luis E. M. Nöel, 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. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Rocha, Sayonarah C. Pessoa, Marco T. C. Neves, Luiza D. R. Alves, Silmara L. G. Silva, Luciana M. Santos, Hérica L. Oliveira, Soraya M. F. Taranto, Alex G. Comar, Moacyr Gomes, Isabella V. Santos, Fabio V. Paixão, Natasha Quintas, Luis E. M. Nöel, 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. |
| dc.subject.en.pt_BR.fl_str_mv |
Benzylidene digoxin Cancer cells Cardiotonic steroids |
| topic |
Benzylidene digoxin Cancer cells Cardiotonic steroids Glicósidos Cardíacos Glicosídeos Cardíacos |
| dc.subject.es.pt_BR.fl_str_mv |
Glicósidos Cardíacos |
| dc.subject.decs.pt_BR.fl_str_mv |
Glicosídeos Cardíacos |
| description |
Universidade Federal de São João del Rei. Laboratório de Bioquimica Celular. Campus Centro-Oeste Dona Lindú, Divinópolis, MG, Brasil. |
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2014 |
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2014 |
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2015-05-04T17:07:27Z |
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2015-05-04T17:07:27Z |
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info:eu-repo/semantics/article |
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ROCHA, Sayonarah C. et al. 21-Benzylidene Digoxin: A Proapoptotic Cardenolide of Cancer Cells That Up-Regulates Na,K-ATPase and Epithelial Tight Junctions. Plos One, v.9, n.10, 14p, 2014. |
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https://www.arca.fiocruz.br/handle/icict/10192 |
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10.1371/journal.pone.0108776 |
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ROCHA, Sayonarah C. et al. 21-Benzylidene Digoxin: A Proapoptotic Cardenolide of Cancer Cells That Up-Regulates Na,K-ATPase and Epithelial Tight Junctions. Plos One, v.9, n.10, 14p, 2014. 10.1371/journal.pone.0108776 |
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Plos One |
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Plos One |
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