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. What's New? A link between platelets and cancer metastasis has long been recognized. In this paper, the authors provide first evidence that an antiplatelet agent currently in clinical use improves cancer survival in mice. Using ticagrelor, a reversible inhibitor of purinergic P2Y12 receptors critical for platelet activation, they demonstrate that treatment inhibits tumor spread and improves survival in murine B16-F10 melanoma and 4T1 breast cancer metastasis models. Ticagrelor specifically inhibited tumor cell-platelet interactions and decreased tumor cell adhesion by acting primarily on platelets, underscoring a potential clinical use of this and similar agents in cancer therapy in the future.