title: Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis.
abstract: Cancer is often associated with an increased risk of thrombotic events which are exacerbated by treatment with chemotherapeutics such as cyclosphosphamide (CP). Evidence suggests that thrombin can stimulate tumor progression via formation of fibrin and activation of protease-activated receptors (PARs) and platelets. We examined the effect of co-treatment with CP and dabigatran etexilate, a direct inhibitor of thrombin, using the murine orthotopic 4T1 tumor model. Mice receiving co-treatment with both low dose CP and dabigatran etexilate had significantly smaller mammary tumors and fewer lung metastases than mice treated with CP or dabigratran etexilate alone. Co-treatment with dabigatran etexilate and low dose CP also significantly decreased the number of arginase(+)Gr-1(+)CD11b(+) myeloid derived suppressor cells as well as levels of TGF-β in spleens from tumor bearing mice. 4T1 tumors express procoagulant tissue factor (TF) and spontaneously release TF(+) microparticles which are potent procoagulant factors that promote thrombin generation. Treatment with dabigatran etexilate alone prevented tumor-induced increases in circulating TF(+) microparticles and also decreased the numbers of tumor-induced activated platelets by 40%. These results show that co-treatment with dabigatran etexilate and CP synergistically inhibits growth and metastasis of mammary tumors, suggesting that oral administration of the thrombin inhibitor dabigatran etexilate may be beneficial in not only preventing thrombotic events in cancer patients but also in treating malignant tumors themselves.
authors.affiliation: a Lankenau Institute for Medical Research ; Wynnewood , PA USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Alexander
authors.affiliation: a Lankenau Institute for Medical Research ; Wynnewood , PA USA.
authors.forename: Allyson R
authors.initials: AR
authors.lastname: Minton
authors.affiliation: a Lankenau Institute for Medical Research ; Wynnewood , PA USA.
authors.forename: Candace S
authors.initials: CS
authors.lastname: Hayes
authors.affiliation: b Boehringer Ingelheim Pharmaceuticals Inc. ; Ridgefield , CT USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Goss
authors.affiliation: c Boehringer Ingelheim Pharma GmbH & Co. KG ; Biberach an der Riss , Germany.
authors.forename: Joanne
authors.initials: J
authors.lastname: Van Ryn
authors.affiliation: a Lankenau Institute for Medical Research ; Wynnewood , PA USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Gilmour
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D000991:Antithrombins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000378:metabolism; D003520:Cyclophosphamide / Q000494:pharmacology*; D000069604:Dabigatran / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004357:Drug Synergism; D005260:Female; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015539:Platelet Activation / Q000187:drug effects; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013925:Thromboplastin / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000991:Antithrombins; D003520:Cyclophosphamide; D013925:Thromboplastin; D013917:Thrombin; D000069604:Dabigatran
keywords: TGF-β; Thrombin inhibitor; breast cancer; metastasis; microparticles