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Therapeutic levels of aspirin and salicylate directly inhibit a model of angiogenesis through a Cox-independent mechanism

Gillian M. Borthwick^*,1, A. Sarah Johnson¹, Matthew Partington^*, John Burn^*, Robert Wilson and Helen M. Arthur^*,2

^* Institute of Human Genetics, International Centre for Life, University of Newcastle, Newcastle upon Tyne, UK; and

Department of Surgery, James Cook Hospital, University of Durham, Durham, UK

²Correspondence: Institute of Human Genetics, International Centre for Life, University of Newcastle, NE1 3BZ, UK. E-mail helen.arthur{at}ncl.ac.uk

A range of antineoplastic properties is attributed to aspirin, thought to be due to inhibition of cyclooxygenase (Cox) enzymes in tumor cells. One important outcome is that by reducing angiogenic factor secretion by cancer cells, aspirin also inhibits angiogenesis, thereby restricting tumor growth. However, aspirin may also have direct effects on endothelial cells to regulate angiogenesis. Our aim was to quantitate these effects and determine whether they occurred through inhibiting Cox enzymes. The effects of aspirin, salicylate (the natural deacetylated form of aspirin), and the selective Cox inhibitors SC560 and Celecoxib on endothelial cell proliferation, viability, and angiogenesis were compared. Therapeutic aspirin concentrations (0.5 mM) had no detectable effect on endothelial cell viability or proliferation but caused a striking reduction in tubule formation in a three-dimensional collagen angiogenesis assay. This was also seen with equimolar concentrations of salicylate, while selective Cox inhibitors did not inhibit angiogenesis in this assay either alone or in combination. Furthermore, high doses of aspirin or salicylate (5 mM), well above therapeutic plasma concentrations, lead to endothelial cell apoptosis. We conclude that aspirin, at therapeutic concentrations, directly inhibits angiogenesis via a Cox-independent mechanism, which may significantly contribute to its neoplastic protective effects. —Borthwick, G. M., Johnson, A. S., Partington, M., Burn, J., Wilson, R., Arthur, H. M. Therapeutic levels of aspirin and salicylate directly inhibit a model of angiogenesis through a Cox-independent mechanism.

Key Words: endothelial cells • Celecoxib • SC560 • cancer

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