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

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.

A systematic review on the effects of direct oral anticoagulants on cancer growth and metastasis in animal models

“…n.descr., not described in paper; no., number; i.p., intraperitoneal; i.v., intravenous; s.c., subcutaneous. [29][30][31][32], two studies reported on rivaroxaban (both 2019) [24,25], and one study reported on both dabigatran etexilate and rivaroxaban (2019) [23].…”

“…The 9 selected publications included a total of 19 in vivo experiments (Table 1). Experiments were conducted in mice (n = 18) or rats (n = 1) of both male and female sex; and included carcinogenicity studies [28], spontaneous breast cancer [24], subcutaneous (fibrosarcoma [24], colorectal [24] and pancreatic cancer [25]), orthotopic (pancreatic [28,32] and breast cancer [29,31,23]) and experimental metastasis models (melanoma [27] and ovarian cancer [30]). The number of animals per treatment group ranged from 4 to 50.…”

“…In a syngeneic pancreatic cancer model, Shi et al also tested the effects of dabigatran etexilate treatment (80 mg/kg, twice daily, oral gavage; n = 7-8) [32]. Treatment was started seven days after orthotopic inoculation of 4 × 10 5 Panc02 murine pancreatic cancer cells in the pancreas.…”

“…Treatment was started seven days after orthotopic inoculation of 4 × 10 5 Panc02 murine pancreatic cancer cells in the pancreas. Three weeks after cancer cell inoculation, vehicle and dabigatran etexilate-treated mice were euthanized and it was shown that dabigatran etexilate monotherapy did not affect primary tumor growth (measured as tumor weight and volume) when compared to vehicle-treated mice [32]. However, dabigatran etexilate treatment increased the number of intratumoral CD31-positive blood vessels and increased the percentage of Ki67-positive tumor cells.…”

Decreasing Tumor Growth and Angiogenesis by Inhibition of Coagulation

“…18 An additional study has reported that dabigatran potentiates gemcitabine-induced growth inhibition of pancreatic cancer but does not affect primary tumor growth when used as monotherapy. 19 Similar to the abovedelineated anticoagulants, apixaban used at a high dose (five times the therapeutic dose) has been found to interfere with cancer cell function in vitro, reducing proliferation and increasing apoptosis in several cancer cell lines. 20 Previously published data demonstrated a favorable effect of warfarin on survival of patients with non-small cell lung cancer, although such effect was not found in other investigated malignancies, including colon, prostate, and head and neck cancers.…”