Abstract
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 9 FAP patients and healthy controls, pairmatched for gender and age, we compared systemic biosynthesis of PGI2, thromboxane(TX)A2 and prostaglandin(PG)E2(assessing urinary enzymatic metabolites, PGI-M, TX-M and PGE-M, respectively). The impact of celecoxib (400mg/BID 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, unaffected by celecoxib; thus suggesting the involvement of a COX-1-dependent pathway, presumably from platelets. This was supported by the finding that in co-cultures of human colon adenocarcinoma cell line(HT-29) and platelets, enhancedTXA2 generation was almost completely inhibited by pre-treatment 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 pro-angiogenesis proteins but also the anti-angiogenic TIMP-2. Urinary PGI-M, but not PGE-M, was negatively correlated with circulating levels of FGF-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.
- Received December 5, 2011.
- Revision received December 31, 2011.
- Accepted January 18, 2012.
- The American Society for Pharmacology and Experimental Therapeutics