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 receptor (PAR-1) by cleaving the receptor's N-terminal end. In several human cancers, PAR1 expression and activation correlates with tumor progression and metastatization. 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 confirmed that exposure of tumor cells to thrombin significantly increased cell proliferation and this was coupled with downregulation of p27 and concomitant induction of cyclin D1. Dabigatran was consistently effective in antagonizing thrombin-induced proliferation as well as it restored the baseline pattern of cell cycle protein expression. Thrombin significantly upregulated the expression of proangiogenetic proteins like Twist and GRO-α in human umbilical vascular endothelial cells (HUVEC) cells and their expression was significantly 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.
Department of Medicine, University of Padova School of Medicine, Padova, Italy. fabrizio.vianello@unipd.it.
Fabrizio
F
Vianello
Department of Medicine, University of Padova School of Medicine, Padova, Italy.
Luisa
L
Sambado
Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Deutschland, Germany.
Ashley
A
Goss
Department of Medicine, University of Padova School of Medicine, Padova, Italy.
Fabrizio
F
Fabris
Department of Cardiologic, Thoracic and Vascular Sciences, University of Padova School of Medicine, Padova, Italy.
Paolo
P
Prandoni
D000991:Antithrombins / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D000069604:Dabigatran / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000991:Antithrombins; C530104:CCND1 protein, human; C436291:CDKN1B protein, human; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D013917:Thrombin; D000069604:Dabigatran
Cancer; PAR-1; dabigatran; thrombin