Effects of celecoxib on prostanoid biosynthesis and circulating angiogenesis proteins in familial adenomatous polyposis.

Abstract

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.

• Authors: Melania Dovizio, Stefania Tacconelli, Emanuela Ricciotti, Annalisa Bruno, Thorsten Jürgen Maier, Paola Anzellotti, Luigia Di Francesco, Paola Sala, Stefano Signoroni, Lucio Bertario, Dan A Dixon, John A Lawson, Dieter Steinhilber, Garret A FitzGerald, Paola Patrignani
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 341 Issue 1 Pg. 242-50 (Apr 2012) ISSN: 1521-0103 [Electronic] United States
• PMID: 22262921 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Prostaglandins
• Pyrazoles
• Sulfonamides
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Thromboxane A2
• Epoprostenol
• Celecoxib

Topics

• Adenomatous Polyposis Coli (blood, drug therapy)
• Adult
• Animals
• Celecoxib
• Cyclooxygenase 2 Inhibitors (pharmacology, therapeutic use)
• Epoprostenol (antagonists & inhibitors, biosynthesis)
• Female
• HT29 Cells
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Middle Aged
• Neovascularization, Physiologic (drug effects, physiology)
• Prostaglandins (biosynthesis, blood)
• Pyrazoles (pharmacology, therapeutic use)
• Sulfonamides (pharmacology, therapeutic use)
• Thromboxane A2 (antagonists & inhibitors, biosynthesis)
• Treatment Outcome
• Vascular Endothelial Growth Factor A (blood)