Thrombin inhibition and cisplatin block tumor progression in ovarian cancer by alleviating the immunosuppressive microenvironment

Abstract

Cancer is often associated with an increased risk of thrombotic complications which can be aggravated by treatment with chemotherapeutics such as cisplatin. Multiple lines of evidence suggest that thrombin activity promotes tumor growth and metastasis. We examined the effect of co-treatment with dabigatran etexilate, a direct thrombin inhibitor, and cisplatin using the murine ID8 ovarian cancer model. Mice receiving co-treatment with both dabigatran etexilate and low dose cisplatin had significantly smaller tumors, developed less ascites and had lower levels of circulating activated platelets and tissue factor (TF) positive microparticles than those treated with dabigatran etexilate or cisplatin alone. Co-treatment with dabigatran etexilate and cisplatin significantly decreased the number of Gr1+/CD11b+ myeloid derived suppresser cells and CD11b+/CD11c+ dendritic cells in the ascites of ID8 tumor-bearing mice. Co-treatment also significantly reduced levels of pro-tumorigenic cytokines including TGF-β, VEGF, IL-6, IL-10, and MCP-1 in the ascites while increasing IFN-γ production by CD8+ effector T cells in the tumor ascites. These results demonstrate that co-treatment with dabigatran etexilate significantly augments the anti-tumor activity of cisplatin in ovarian tumor progression by alleviating the immunosuppressive microenvironment, suggesting that thrombin may be a potential therapeutic target for treatment of ovarian cancer.

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

“…The increase of aberrant or collapsed vessels in tumors of dabigatran-treated mice combined with bleeding in these mice likely explains the increased dissemination. Importantly, dabigatran-induced bleeding seems specific for pancreatic cancer, as the dabigatran dose used (i.e., 80 mg/kg, twice daily) is well tolerated and did not induce bleeding in an ovarian cancer model (25), whereas longterm treatment with a dose of 140 mg/kg (administered via oral gavage) is safe and did not induce bleeding in models of allergic lung inflammation (26), highfat-diet-induced fatty liver disease (27) and glial activation (28). Dabigatraninduced bleeding in our orthotopic pancreatic cancer model is probably due to the fact that orthotopically grown pancreatic tumors are already prone to…”

“…Tumor cells (4 × 10 5 in 50 μL PBS) were injected directly into the tail of the pancreas under anesthesia. Dabigatran (BIBR1048, at a dose of 80 mg/kg in 0.5% Natrosol solution, as suggested by the manufacturer and shown to be well tolerated in mice [25][26][27][28]) or 0.5% Natrosol solution (placebo control) was administered by oral gavage twice daily starting from 7 d after tumor cell injection. If indicated, mice were treated with gemcitabine (100 mg/kg in PBS, intraperitoneal) or PBS (control) starting from 7 d after tumor cell injection, and this treatment was repeated twice weekly.…”

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.…”

“…Alexander et al also tested the effects of dabigatran etexilate treatment (oral gavage twice daily 80 mg/kg, Monday through Friday and over the weekends on dabigatran etexilate supplemented chow diet, 10 mg/g chow) in another syngeneic mouse model, which encompassed intraperitoneal injection of 1 × 10 6 luciferase transfected ID-8 (ID8-luc) mouse ovarian cancer cells [30]. Bioluminescence imaging was used to monitor and quantify tumor cells in the peritoneal cavity, and when bioluminescence values were approximately 5 × 10 5 photons/s/cm 2 , treatment with dabigatran etexilate was initiated.…”