Identification and characterization of Cardiac Glycosides as senolytic compounds

Francisco Triana-Martínez, Pilar Picallos-Rabina, Sabela Da Silva-Álvarez, Federico Pietrocola, Susana Llanos, Verónica Rodilla, Enrica Soprano, Pablo Pedrosa, Alba Ferreirós, Marta Barradas, Fernanda Hernández-González, Marta Lalinde, Neus Prats, Cristina Bernadó, Patricia González, María Gómez, Maria P. Ikonomopoulou, Pablo J. Fernández-Marcos, Tomás García-Caballero, Pablo Pino, Joaquín Arribas, Anxo Vidal, Miguel González-Barcia, Manuel Serrano, María I. Loza, Eduardo Domínguez () and Manuel Collado ()
Additional contact information
Francisco Triana-Martínez: Health Research Institute of Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS)
Pilar Picallos-Rabina: Health Research Institute of Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS)
Sabela Da Silva-Álvarez: Health Research Institute of Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS)
Federico Pietrocola: The Barcelona Institute of Science and Technology (BIST)
Susana Llanos: DNA Replication Group, Spanish National Cancer Research Centre (CNIO)
Verónica Rodilla: Vall d´Hebron Institute of Oncology (VHIO) and CIBERONC
Enrica Soprano: Universidade de Santiago de Compostela
Pablo Pedrosa: Health Research Institute of Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS)
Alba Ferreirós: Health Research Institute of Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS)
Marta Barradas: Madrid Institute for Advanced Studies (IMDEA) in Food, CEI UAM+CSIC
Fernanda Hernández-González: The Barcelona Institute of Science and Technology (BIST)
Marta Lalinde: Vall d´Hebron Institute of Oncology (VHIO) and CIBERONC
Neus Prats: The Barcelona Institute of Science and Technology (BIST)
Cristina Bernadó: Vall d´Hebron Institute of Oncology (VHIO) and CIBERONC
Patricia González: Spanish National Cancer Research Centre (CNIO)
María Gómez: Spanish National Cancer Research Centre (CNIO)
Maria P. Ikonomopoulou: Madrid Institute for Advanced Studies (IMDEA) in Food, CEI UAM+CSIC
Pablo J. Fernández-Marcos: Madrid Institute for Advanced Studies (IMDEA) in Food, CEI UAM+CSIC
Tomás García-Caballero: Facultad de Medicina. USC. Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS)
Pablo Pino: Universidade de Santiago de Compostela
Joaquín Arribas: Vall d´Hebron Institute of Oncology (VHIO) and CIBERONC
Anxo Vidal: CiCLOn, Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS)
Miguel González-Barcia: Servicio de Farmacia, Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS)
Manuel Serrano: The Barcelona Institute of Science and Technology (BIST)
María I. Loza: BioFarma, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Health Research Institute of Santiago de Compostela (IDIS)
Eduardo Domínguez: BioFarma, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Health Research Institute of Santiago de Compostela (IDIS)
Manuel Collado: Health Research Institute of Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS)

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification. Senescent cells present a slightly depolarized plasma membrane and higher concentrations of H+, making them more susceptible to the action of CGs. These vulnerabilities can be exploited for therapeutic purposes as evidenced by the in vivo eradication of tumors xenografted in mice after treatment with the combination of a senogenic and a senolytic drug. The senolytic effect of CGs is also effective in the elimination of senescence-induced lung fibrosis. This experimental approach allows the identification of compounds with senolytic activity that could potentially be used to develop effective treatments against age-related diseases.

Date: 2019
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DOI: 10.1038/s41467-019-12888-x

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