1. Identification and characterization of Cardiac Glycosides as senolytic compounds.
- Author
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Triana-Martínez F, Picallos-Rabina P, Da Silva-Álvarez S, Pietrocola F, Llanos S, Rodilla V, Soprano E, Pedrosa P, Ferreirós A, Barradas M, Hernández-González F, Lalinde M, Prats N, Bernadó C, González P, Gómez M, Ikonomopoulou MP, Fernández-Marcos PJ, García-Caballero T, Del Pino P, Arribas J, Vidal A, González-Barcia M, Serrano M, Loza MI, Domínguez E, and Collado M
- Subjects
- A549 Cells, Animals, Antibiotics, Antineoplastic pharmacology, Bleomycin pharmacology, Breast Neoplasms, Cell Line, Tumor, Cell Membrane drug effects, Digoxin pharmacology, Female, Humans, Hydrogen-Ion Concentration drug effects, Mice, Osteoarthritis, Ouabain pharmacology, Proscillaridin pharmacology, Pulmonary Fibrosis, Xenograft Model Antitumor Assays, Apoptosis drug effects, Cardiac Glycosides pharmacology, Cellular Senescence drug effects, Chondrocytes drug effects, Fibroblasts drug effects
- 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.
- Published
- 2019
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