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

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

Research output: Contribution to journalArticlepeer-review

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 (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.

Original languageEnglish
Pages (from-to)242-250
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume341
Issue number1
DOIs
Publication statusPublished - Apr 2012

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

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