Identification and characterization of Digoxin as a novel senolytic drug

Resumo

Cellular senescence is a potent protective response against several potentially dangerous stimuli that prevent the progression of damaged cells by inducing a stable proliferative arrest. In this way, cancer cells need to avoid this response in order to grow and form tumors. Thus, we can consider cellular senescence as an essential antitumor mechanism. Restoring this response in tumor cells has been shown to have a positive impact in cancer treatment, since various therapies can induce senescence in tumors, preventing their growth. However, in recent years it has been described that senescent cells remain active and secrete a large number of factors to their environment with antagonistic activities. In some cases, these factors may have a reinforcing effect on senescence, but in other cases they may have a protumoral activity. At the same time, senescent cells accumulate in the organism over time and contribute to the functional deterioration of the tissues, mainly due to the action of these same secreted factors. This contribution to the aging of senescent cells has sparked interest in the identification of compounds capable of selectively eliminating senescent cells, the so-called senolytic compounds. In this thesis, we performed a high-throughput screening of a chemical library to identify novel senolytic compounds. In this way, we identified the family of Cardiac Glycosides, and in particular Digoxin, as a promising senolytic drug. We also characterized the potential mechanisms behind the senolytic effect of Digoxin.