Use of dabigatran etexilate to reduce breast cancer progression.
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.
DeFeo
Karen
K
Lankenau Institute for Medical Research, Wynnewood, PA, USA.
Hayes
Candace
C
Chernick
Michael
M
Ryn
Joanne Van
JV
Gilmour
Susan K
SK
D000818:Animals; D058833:Antithrombin Proteins / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D000069604:Dabigatran; D018450:Disease Progression; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D013917:Thrombin / Q000037:antagonists & inhibitors; D014132:Trachea / Q000637:transplantation
D058833:Antithrombin Proteins; D001562:Benzimidazoles; D011725:Pyridines; D013917:Thrombin; D000069604:Dabigatran