Senolysis Reduces Senescence in Veins and Cancer Cell Migration

Abstract

AbstractSenescence is a persistent state of cell cycle arrest. Induction of senescence has been explored as a barrier against tumor progression and is used as a therapeutic option. Despite the advantages of the introduction of senescence‐inducing compounds in the clinic, recent studies show that their side‐effects can be partially masking their antitumor potential. This is due to the deleterious effects that accumulation of senescent cells in tissues and organs causes on tissue microenvironment that confer tumor‐promoting properties. In this study, it is demonstrated that the presence of senescent endothelium favors cancer cell migration and show that palbociclib systemic treatment induces senescence in veins in an orthotopic triple‐negative breast cancer mouse model. Moreover, it is found that following palbociclib‐induced senogenesis, the elimination of senescent cells using the nanoencapsulated senolytic navitoclax (NP(nav)‐Gal) produces the selective elimination of endothelial senescent cells and induces a marked recovery of endothelial tissue functionality. Finally, the treatment with NP(nav)‐Gal produces a significant decrease of senescence in veins which is consistent with the decrease in metastasic burden observed. These results evidence the potential of reducing vascular senescence using senolytic therapies as a strategy to limit the metastatic dissemination of tumors cells in breast cancer patients subjected to chemotherapeutic treatments.