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Molecular Medicine

, Volume 23, Issue 1, pp 13–23 | Cite as

Dabigatran Potentiates Gemcitabine-Induced Growth Inhibition of Pancreatic Cancer in Mice

  • Kun Shi
  • Helene Damhofer
  • Joost Daalhuisen
  • Marieke ten Brink
  • Dick J. Richel
  • C. Arnold Spek
Research Article

Abstract

Pancreatic cancer is one of the most lethal solid malignancies, with few treatment options. We have recently shown that expression of protease activated receptor (PAR)-1 in the tumor microenvironment drives the progression and induces the chemoresistance of pancreatic cancer. As thrombin is the prototypical PAR-1 agonist, here we address the effects 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 monotherapy.

Notes

Acknowledgments

Dabigatran was kindly provided by Dr. Ashley Goss from the CardioMetabolic Disease Research department of Boehringer Ingelheim Pharmaceuticals. This study is supported by grants from the Dutch Cancer Foundation (2009–4324 and 2014–6782).

Supplementary material

10020_2017_2301013_MOESM1_ESM.pdf (109 kb)
Supplementary material, approximately 108 KB.

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Authors and Affiliations

  • Kun Shi
    • 1
  • Helene Damhofer
    • 2
  • Joost Daalhuisen
    • 1
  • Marieke ten Brink
    • 1
  • Dick J. Richel
    • 3
  • C. Arnold Spek
    • 1
  1. 1.Center for Experimental and Molecular Medicine, H2-215, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  2. 2.Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  3. 3.Department of Medical Oncology, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands

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