Identification and characterization of Cardiac Glycosides as senolytic compounds
| Autor: | Verónica Rodilla, Pablo J. Fernandez-Marcos, Marta Barradas, Manuel Collado, Marta Lalinde, Patricia González, Cristina Bernadó, Fernanda Hernández-González, Francisco Triana-Martínez, Joaquín Arribas, Maria P. Ikonomopoulou, Manuel Serrano, Miguel González-Barcia, Federico Pietrocola, María Elena Pardo Gómez, Eduardo Domínguez, Sabela Da Silva-Álvarez, Anxo Vidal, María Isabel Loza, Pablo del Pino, Pablo Pedrosa, Pilar Picallos-Rabina, Neus Prats, Alba Ferreirós, Tomás García-Caballero, Enrica Soprano, Susana Llanos |
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| Přispěvatelé: | IMDEA Food Institute, Fundación Ramón Areces, Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal, European Molecular Biology Organization, Ministerio de Economía y Competitividad (España), Unión Europea, European Research Council, Fundación La Caixa |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Digoxin Pulmonary Fibrosis ATPase Cell General Physics and Astronomy Apoptosis Pharmacology Mice 0302 clinical medicine Cytotoxic T cell lcsh:Science Ouabain Cellular Senescence Antibiotics Antineoplastic Multidisciplinary biology Chemistry Depolarization Hydrogen-Ion Concentration 3. Good health medicine.anatomical_structure Proscillaridin 030220 oncology & carcinogenesis Female Science Breast Neoplasms Drug development Senescence Article General Biochemistry Genetics and Molecular Biology Cardiac Glycosides Bleomycin 03 medical and health sciences Chondrocytes In vivo Cell Line Tumor Osteoarthritis medicine Animals Humans Senolytic A549 cell Cell Membrane General Chemistry Fibroblasts Xenograft Model Antitumor Assays 030104 developmental biology A549 Cells Cell culture biology.protein lcsh:Q |
| Zdroj: | Nature Communications Nature Communications, Vol 10, Iss 1, Pp 1-12 (2019) DOAJ-Articles PubMed Central Repisalud Instituto de Salud Carlos III (ISCIII) |
| ISSN: | 2041-1723 |
| Popis: | 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. We thank Matthias Drosten, Alejo Efeyan and Sean Morrison for plasmids. F.T-M. is a postdoctoral fellow from CONACYT (cvu 268632); P.P. is a predoctoral fellow from Xunta de Galicia; M.C. is a "Miguel Servet II" investigator (CPII16/00015). P.P.-R. receives support from a program by the Deputacion de Coruna (BINV-CS/2019). Work in the laboratory of M.C. is funded by grant RTI2018-095818-B-100 (MCIU/AEI/FEDER, UE). P.J.F.-M. is funded by the IMDEA Food Institute, the Ramon Areces Foundation, (CIVP18A3891), and a Ramon y Cajal Award (MICINN) (RYC-2017-22335). M.P.I. is funded by Talento Modalidad-1 Program Grant, Madrid Regional Government (#2018-T1/BIO-11262). F.P. was funded by a Long Term EMBO Fellowship (ALTF-358-2017) and F.H-G. was funded by the PhD4MD Programme of the IRB, Hospital Clinic and IDIBAPS. Work in the laboratory of M.S. was funded by the IRB and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (ERDF) (SAF2013-48256-R), the European Research Council (ERC-2014-AdG/669622), and "laCaixa" Foundation. Sí |
| Databáze: | OpenAIRE |
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