title: 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.affiliation: Department of Medicine and Aging, G. d'Annunzio University School of Medicine, 31 66100, Chieti, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Dovizio
authors.forename: Stefania
authors.initials: S
authors.lastname: Tacconelli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ricciotti
authors.forename: Annalisa
authors.initials: A
authors.lastname: Bruno
authors.forename: Thorsten Jürgen
authors.initials: TJ
authors.lastname: Maier
authors.forename: Paola
authors.initials: P
authors.lastname: Anzellotti
authors.forename: Luigia
authors.initials: L
authors.lastname: Di Francesco
authors.forename: Paola
authors.initials: P
authors.lastname: Sala
authors.forename: Stefano
authors.initials: S
authors.lastname: Signoroni
authors.forename: Lucio
authors.initials: L
authors.lastname: Bertario
authors.forename: Dan A
authors.initials: DA
authors.lastname: Dixon
authors.forename: John A
authors.initials: JA
authors.lastname: Lawson
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
authors.forename: Paola
authors.initials: P
authors.lastname: Patrignani
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000097:blood* / Q000188:drug therapy; D000328:Adult; D000818:Animals; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005260:Female; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011453:Prostaglandins / Q000096:biosynthesis* / Q000097:blood; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013928:Thromboxane A2; D011464:Epoprostenol; D000068579:Celecoxib