discover this Aspirin acetylsalicylic acid belongs to the

Aspirin (acetylsalicylic acid) belongs to the family of nonsteroidal anti-inflammatory drugs (NSAIDs) which share common therapeutic and side-effects through the inhibition of COX-1 and COX-2 (). Aspirin is the only NSAID which causes an irreversible inactivation of COX-isozymes through acetylation of strategically located serine residues, , Ser529 and Ser516 in human COX‐1 and COX‐2, respectively. The drug is 60-fold more potent to inhibit platelet COX-1 than monocyte COX-2, (). It has a short half-life (~20min), due to a rapid hydrolysis to salicylic discover this by plasma/tissue esterases and first pass hepatic metabolism. Its metabolite salicylic acid has a longer half-life (~2–4.5h) but is not an efficient inhibitor of COX‐isozyme activity. Aspirin is administered at low-doses (75–100mg daily) for the prevention of atherothrombosis (). The administration of enteric-coated aspirin 100mg/day is associated with systemic plasma concentrations of acetylsalicylic acid and salicylic acid in the μmolar range (, 4μM and 40μM, respectively) (). Daily low-dose aspirin causes a complete suppression of platelet COX-1 activity which is associated with saturation of the antiplatelet inhibitory effect (). Due to irreversible COX-1 inactivation and the fact that platelets have limited capacity for de novo protein synthesis, the administration of low-dose aspirin every 24h causes a complete and persistent inhibition of COX-1 in platelets associated with a limited and rapidly reversible inhibitory effect on COX-2 expressed in nucleated cells (). Consequently, persistent inhibition of COX-2 activity by aspirin requires the administration of higher and repeated daily doses (). Based on clinical pharmacology data, the administration of two or more standard (325mg) aspirin tablets per week used in the study by seems to be incompatible with an inhibitory effect of the drug on COX-2-dependent prostanoids produced by nucleated intestinal epithelial cells. In contrast, this aspirin administration schedule might have indirectly down-regulated COX-2 expression in colonic epithelial cells through the inhibition of platelet function (). In fact, platelet-derived products may regulate COX-2 induction in colorectal epithelial cells and stromal cells (). verified the possible direct effect of aspirin on COX-2-dependent EGFR induction by performing experiments using epithelial cells isolated from intestinal polyps of APC mice which express high levels of COX-2 and EGFR and normal epithelial cells. These cells were treated with either aspirin (1–4mM) or the selective COX-2 inhibitor celecoxib (10–40μM) and a profound down-regulation of EGFR protein levels was found only at the highest concentrations of the two drugs. Differently from the data obtained in FAP patients, where aspirin was administered , the drug did not affect COX-2 protein levels . It is noteworthy that the concentrations of aspirin and celecoxib used were several folds higher than those reached at therapeutic doses in humans. These results may suggest the role of COX-independent mechanism in EGFR downregulation detected by high concentration of the drugs, plausibly through a direct inhibitory effect on the activation of AP-1 activity (). Previous studies have shown the possible interplay between COX-2 and EGFR. Thus, COX-2 derived prostanoids cause transactivation of the EGFR kinase cascade in colon cancer cells () whereas the activation of EGFR can stimulate COX-2 biosynthesis (). The study by reveals a novel functional association between COX-2 and EGFR during colorectal carcinogenesis, and provides the rational for aspirin as an adjuvant treatment to improve the efficacy of EGFR inhibitors in CRC. Clinical studies should be performed to verify whether the coadministration of low-dose aspirin and possibly other antiplatelet agents, such as P2Y12 antagonists, may lead to overcome the resistance to EGFR inhibitors in cancer treatment. Conflict of Interest Statement