PT  - JOURNAL ARTICLE
AU  - Melania Dovizio
AU  - Stefania Tacconelli
AU  - Emanuela Ricciotti
AU  - Annalisa Bruno
AU  - Thorsten Jürgen Maier
AU  - Paola Anzellotti
AU  - Luigia Di Francesco
AU  - Paola Sala
AU  - Stefano Signoroni
AU  - Lucio Bertario
AU  - Dan A. Dixon
AU  - John A. Lawson
AU  - Dieter Steinhilber
AU  - Garret A. FitzGerald
AU  - Paola Patrignani
TI  - Effects of Celecoxib on Prostanoid Biosynthesis and Circulating Angiogenesis Proteins in Familial Adenomatous Polyposis
AID  - 10.1124/jpet.111.190785
DP  - 2012 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 242--250
VI  - 341
IP  - 1
4099  - http://jpet.aspetjournals.org/content/341/1/242.short
4100  - http://jpet.aspetjournals.org/content/341/1/242.full
SO  - J Pharmacol Exp Ther2012 Apr 01; 341
AB  - Vascular cyclooxygenase (COX)-2-dependent prostacyclin (PGI2) 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 PGI2 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 PGI2, thromboxane (TX) A2, and prostaglandin (PG) E2, assessing their urinary enzymatic metabolites, 2,3-dinor-6-keto PGF1α (PGI-M), 11-dehydro-TXB2 (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 TXA2 generation was almost completely inhibited by pretreatment of platelets with aspirin, a preferential inhibitor of COX-1. In FAP, celecoxib profoundly suppressed PGE2 and PGI2 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 PGE2 by celecoxib may reduce tumor progression. However, the coincident depression of vascular PGI2, in a context of enhanced TXA2 biosynthesis, may modulate the attendant angiogenesis, contributing to variability in the chemopreventive efficacy of COX-2 inhibitors such as celecoxib.