Ticagrelor inhibits platelet–tumor cell interactions and metastasis in human and murine breast cancer

  • Alison J. Gareau
  • Colin Brien
  • Simon Gebremeskel
  • Robert S. Liwski
  • Brent Johnston
  • Michael Bezuhly
Research Paper

Abstract

Activated platelets promote the proliferation and metastatic potential of cancer cells. Platelet activation is largely mediated through ADP engagement of purinergic P2Y12 receptors on platelets. We examined the potential of the reversible P2Y12 inhibitor ticagrelor, an agent used clinically to prevent cardiovascular and cerebrovascular events, to reduce tumor growth and metastasis. In vitro, MCF-7, MDA-MB-468, and MDA-MB-231 human mammary carcinoma cells exhibited decreased interaction with platelets treated with ticagrelor compared to untreated platelets. Prevention of tumor cell–platelet interactions through pretreatment of platelets with ticagrelor did not improve natural killer cell-mediated tumor cell killing of K562 myelogenous leukemia target cells. Additionally, ticagrelor had no effect on proliferation of 4T1 mouse mammary carcinoma cells co-cultured with platelets, or on primary 4T1 tumor growth. In an orthotopic 4T1 breast cancer model, ticagrelor (10 mg/kg), but not clopidogrel (10 mg/kg) or saline, resulted in reduced metastasis and improved survival. Ticagrelor treatment was associated with a marked reduction in tumor cell–platelet aggregates in the lungs at 10, 30 and 60 min post-intravenous inoculation. These findings suggest a role for P2Y12-mediated platelet activation in promoting metastasis, and provide support for the use of ticagrelor in the prevention of breast cancer spread.

Keywords

Platelets Ticagrelor P2Y12 Breast cancer Metastasis Natural killer cells 

Notes

Acknowledgements

The authors would like to thank Terry LeVatte for technical assistance. This research was funded by the Canadian Breast Cancer Foundation and the Dalhousie University Department of Surgery. C. Brien and A. Gareau were supported by a Cancer Research Training Program studentship and an Izaak Walton Killam Health Centre post-graduate fellowship, respectively.

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Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Microbiology & ImmunologyDalhousie UniversityHalifaxCanada
  2. 2.Izaak Walton Killam Health CentreHalifaxCanada
  3. 3.School of MedicineUniversity College CorkCorkIreland
  4. 4.Department of PathologyDalhousie UniversityHalifaxCanada
  5. 5.Department of PediatricsDalhousie UniversityHalifaxCanada
  6. 6.Division of Plastic and Reconstructive Surgery, Department of SurgeryDalhousie UniversityHalifaxCanada
  7. 7.Department of SurgeryDalhousie University, IWK Health CentreHalifaxCanada

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