Dabigatran antagonizes growth, cell-cycle progression, migration, and endothelial tube formation induced by thrombin in breast and glioblastoma cell lines

Thrombin activates its G-coupled seven transmembrane protease-activated recep- tor (PAR-1) by cleaving the receptor’s N-terminal end. In several human cancers, PAR-1 expression and activation correlates with tumor progression and metasta- tization. This provides compelling evidence for the effectiveness of an appropriate antithrombin agent for the adjuvant treatment of patients with cancer. Dabigatran is a selective direct thrombin inhibitor that reversibly binds to thrombin. In this study, we aimed to explore if dabigatran may affect mechanisms favoring tumor growth by interfering with thrombin-induced PAR-1 activation. We con rmed that exposure of tumor cells to thrombin signi cantly increased cell proliferation and this was coupled with downregulation of p27 and con- comitant induction of cyclin D1. Dabigatran was consistently effective in an- tagonizing thrombin-induced proliferation as well as it restored the baseline pattern of cell cycle protein expression. Thrombin signi cantly upregulated the expression of proangiogenetic proteins like Twist and GRO-α in human umbili- cal vascular endothelial cells (HUVEC) cells and their expression was signi cantly brought down to control levels when dabigatran was added to culture. We also found that the chemoattractant effect of thrombin on tumor cells was lost in the presence of dabigatran, and that the thrombin antagonist was effective in dampening vascular tube formation induced by thrombin. Our data support a role of thrombin in inducing the proliferation, migration, and proangiogenetic effects of tumor cells in vitro. Dabigatran has activity in antagonizing all these effects, thereby impairing tumor growth and progression. In vivo models may help to understand the relevance of this pathway