Dabigatran potentiates gemcitabine-induced growth inhibition of pancreatic cancer in mice.
Pancreatic cancer is one of the most lethal solid malignancies with little treatment options. We have recently shown that expression of protease activated receptor (PAR)-1 in the tumor microenvironment drives progression and induces chemoresistance of pancreatic cancer. As thrombin is the prototypical PAR-1 agonist, here we addressed the effect of the direct thrombin inhibitor dabigatran on pancreatic cancer growth and drug resistance in an orthotropic pancreatic cancer model. We show that dabigatran treatment did not affect primary tumor growth whereas it significantly increased tumor dissemination throughout the peritoneal cavity. Increased dissemination was accompanied by intratumoral bleeding and increased numbers of aberrant and/or collapsed blood vessels in the primary tumors. In combination with gemcitabine, dabigatran treatment limited primary tumor growth, did not induce bleeding complications and prevented tumor cell dissemination. Dabigatran was however not as efficient as genetic ablation of PAR-1 in our previous study suggesting that thrombin is not the main PAR-1 agonist in the setting of pancreatic cancer. Overall, we show that dabigatran potentiates gemcitabine-induced growth inhibition of pancreatic cancer but does not affect primary tumor growth when used as a monotherapy.
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
Kun
K
Shi
Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Helene
H
Damhofer
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
Joost
J
Daalhuisen
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
Marieke
M
Ten Brink
Department of Medical Oncology, Academic Medical Center, Amsterdam, the Netherlands.
Dick J
DJ
Richel
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
C Arnold
CA
Spek
Pancreatic cancer; coagulation; dabigatran; mice; thrombin