Use of dabigatran etexilate to reduce breast cancer progression

Abstract

Coagulation proteases and the generation of thrombin are increased in breast tumor epithelial and stromal cells. Since thrombin can modify tumor cell behavior directly through the activation of protease-activated receptors (PARs) or indirectly by generating fibrin matrices, the effect of dabigatran etexilate, a direct thrombin inhibitor, on breast cancer development was evaluated. Dabigatran inhibited invasiveness of MDA-MB-231 breast carcinoma cells across Matrigel-coated membranes at concentrations that had no effect on the proliferation index of cultured tumor cells. In vivo evaluation of invasiveness of MDA-MB-231 cells in tracheal xenotransplants in nude mice orally administered dabigatran etexilate twice daily at a dose of 45 mg/kg over 4 weeks demonstrated less invasion of tumor cells through the tracheal wall compared to vehicle-treated mice. To evaluate the effect of dabigatran on the development of metastatic foci, 4T1 tumor cells were injected orthotopically in the mammary fat pads of syngeneic Balb/c mice. Dabigatran etexilate treatment exhibited evidence of antitumor activity with a 50% reduction in tumor volume at 4 weeks following orthotopic injection of 4T1 cells in syngeneic Balb/c mice with no weight loss in treated mice. Dabigatran etexilate reduced both 4T1 tumor cells in the blood and liver micrometastases by 50-60%. These results suggest that oral administration of the direct thrombin inhibitor, dabigatran etexilate, inhibits both invasion and metastasis of malignant breast tumors, suggesting that it may be beneficial in not only preventing thrombotic events in cancer patients, but also as adjunct therapy to treat malignant tumors.

Changes in the expression of plasma proteins associated with thrombosis in BRCA1 mutation carriers

“…Thrombosis is also beginning to be associated with breast cancer. In this regard, coagulation-related proteases and thrombin generation have been shown increased in breast tumor epithelial and stromal cells (Defeo et al 2010;McEachron et al 2010). However, in our knowledge, it has not been yet explored whether carriers of BRCA1 mutations may have altered circulating proteins associated with a pro-thrombotic state.…”

Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis

“…Whereas we previously reported that treatment with dabigatran etexilate initiated before orthotopic injection of 4T1 tumor cells inhibited both the growth and metastasis of 4T1 mammary carcinomas, 35 we tested the extent to which treatment with dabigatran and/or low dose cyclophosphamide might exert a therapeutic effect when treatment is initiated after appearance of a palpable primary tumor. Following orthotopic injection of 4T1 tumor cells in the mammary fat pad of Balb/c mice, treatment was initiated when the tumors were between 25-50 mm 3 .…”

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

“…Thrombin promotes cancer cell proliferation and tumor growth [reviewed in 3,19,27,28,41,61]. The latest findings revealed that thrombin-driven colonic adenocarcinoma growth depends on two targets of thrombin-mediated proteolysis: PAR-1, expressed by stromal cells, and the ECM protein, fibrinogen [41].…”

“…Many thrombin or thrombin-dependent substrate inhibitors have been investigated. However, none have been incorporated into clinical oncology practice [19,[25][26][27][28].…”