Vascular cyclooxygenase (COX)-2-dependent prostacyclin (PGI 2) may affect angiogenesis by preventing endothelial activation and platelet release of angiogenic factors present in platelet α-granules. Thus, a profound inhibition of COX-2-dependent PGI 2 might be associated with changes in circulating markers of angiogenesis. We aimed to address this issue by performing a clinical study with celecoxib in familial adenomatous polyposis (FAP). In nine patients with FAP and healthy controls, pair-matched for gender and age, we compared systemic biosynthesis of PGI 2, thromboxane (TX) A 2, and prostaglandin (PG) E 2, assessing their urinary enzymatic metabolites, 2,3-dinor-6-keto PGF 1α (PGI-M), 11-dehydro-TXB 2 (TX-M), and 11-α-hydroxy-9,15-dioxo-2,3,4,5- tetranor-prostane-1,20-dioic acid (PGE-M), respectively. The impact of celecoxib (400 mg b.i.d. for 7 days) on prostanoid biosynthesis and 14 circulating biomarkers of angiogenesis was evaluated in FAP. Intestinal tumorigenesis was associated with enhanced urinary TX-M levels, but unaffected by celecoxib, suggesting the involvement of a COX-1-dependent pathway, presumably from platelets. This was supported by the finding that in cocultures of a human colon adenocarcinoma cell line (HT-29) and platelets enhanced TXA 2 generation was almost completely inhibited by pretreatment of platelets with aspirin, a preferential inhibitor of COX-1. In FAP, celecoxib profoundly suppressed PGE 2 and PGI 2 biosynthesis that was associated with a significant increase in circulating levels of most proangiogenesis proteins but also the antiangiogenic tissue inhibitor of metalloproteinase 2. Urinary PGI-M, but not PGE-M, was negatively correlated with circulating levels of fibroblast growth factor 2 and angiogenin. In conclusion, inhibition of tumor COX-2-dependent PGE 2 by celecoxib may reduce tumor progression. However, the coincident depression of vascular PGI 2, in a context of enhanced TXA 2 biosynthesis, may modulate the attendant angiogenesis, contributing to variability in the chemopreventive efficacy of COX-2 inhibitors such as celecoxib.
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|Publication status||Published - Apr 2012|
ASJC Scopus subject areas
- Molecular Medicine