title: The reversible P2Y12 inhibitor ticagrelor inhibits metastasis and improves survival in mouse models of cancer.
abstract: Tumor cells use activated platelets to promote their proliferation and metastatic potential. Because platelet activation is largely mediated through ADP engagement of purinergic P2Y12 receptors on platelets, we investigated the potential of the reversible P2Y12 inhibitor ticagrelor, a clinical agent used in the prevention of cardiovascular and cerebrovascular events, to inhibit tumor adhesion and metastasis. In B16-F10 melanoma intravenous and intrasplenic metastasis models, mice treated with a clinical dose of ticagrelor (10 mg/kg) exhibited marked reductions in lung (84%) and liver (86%) metastases. Furthermore, ticagrelor treatment improved survival compared to saline-treated animals. A similar effect was observed in a 4T1 breast cancer model, with reductions in lung (55%) and bone marrow (87%) metastases following ticagrelor treatment. In vitro, B16-F10 cells exhibited decreased interaction with platelets from ticagrelor-treated mice compared to saline-treated mice, an effect similar to that observed with blockade of glycoprotein IIbIIIa. Similarly, B16-F10 cells co-incubated with platelets from ticagrelor-treated mice exhibited reduced adhesion to endothelial monolayers compared to those co-incubated with platelets from saline-treated animals, an effect also observed in vivo. Interestingly, pretreatment of endothelial monolayers with ticagrelor did not result in reduced tumor cell adhesion. These findings support a role for P2Y12-mediated platelet activation in promoting metastases, and provide proof-of-concept for the clinical use of ticagrelor in the prevention of tumor metastasis.
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Gebremeskel
authors.forename: Terry
authors.initials: T
authors.lastname: LeVatte
authors.forename: Robert S
authors.initials: RS
authors.lastname: Liwski
authors.forename: Brent
authors.initials: B
authors.lastname: Johnston
authors.forename: Michael
authors.initials: M
authors.lastname: Bezuhly
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015870:Gene Expression; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000556:secondary; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics / Q000378:metabolism; D000077486:Ticagrelor
chemical_list: D000970:Antineoplastic Agents; C548577:P2ry12 protein, mouse; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077486:Ticagrelor; D000241:Adenosine
keywords: ADP receptor; P2Y12; breast cancer; endothelium; melanoma; metastasis; platelet; ticagrelor