Low‐Dose Aspirin Acetylates Cyclooxygenase‐1 in Human Colorectal Mucosa: Implications for the Chemoprevention of Colorectal Cancer

Abstract

The mechanism of action of low-dose aspirin in the prevention of colorectal cancer (CRC) remains largely hypothetical. We aimed to compare the effects of low-dose aspirin (100 mg/day for 7 days) given to 40 individuals undergoing CRC screening on the extent of cyclooxygenase (COX)-1 acetylation at serine-529 (AceCOX-1), in blood platelets vs. colorectal mucosa, at 7 (group 1) and 24 h (group 2) after dosing. A significantly (P < 0.01) lower %AceCOX-1 was detected in colonic and rectal mucosa (average 64%) vs. platelets (average 75%) in both groups. This effect was associated with an average 46% (P < 0.01) and 35% (P < 0.05) reduction in prostaglandin (PG) E 2 levels and phosphorylated S6 (p-S6) levels, respectively. Rectal mucosal levels of p-S6/S6 significantly (P < 0.01) correlated with PGE 2 . These findings demonstrate that low-dose aspirin produces long-lasting acetylation of COX-1 and downregulation of p-S6 in human colorectal mucosa, an effect that may interfere with early colorectal carcinogenesis. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?þ A large body of evidence supports a chemopreventive effect of low-dose aspirin against CRC; however, its cellular target(s) remains largely hypothetical. WHAT QUESTION DID THIS STUDY ADDRESS?þ To what extent and for how long does low-dose aspirin acetylate COX-isozymes in normal colorectal mucosa as compared to blood platelets in subjects undergoing CRC screening.

Clinically Relevant Anti-Inflammatory Agents for Chemoprevention of Colorectal Cancer: New Perspectives

“…The final study mentioned determines cancer preventive efficacy of enteric coated aspirin in Lynch syndrome are dose-responsive by comparing overall cumulative incidence rates of the disease after five years in people who took 100 mg, 300 mg, or 600 mg of the same for at least two years. Low-dose of aspirin use improves overall survival of patients with CRC by modulating various biomarkers [53,54,55,56]. But, in a recent study by Gray et al, [57] reported that low-dose aspirin use did not prolong survival rate in patients with CRC.…”

Perioperative biobehavioral interventions to prevent cancer recurrence through combined inhibition of β‐adrenergic and cyclooxygenase 2 signaling

“…Importantly, although β-blockade and semiselective COX2 inhibition showed beneficial effects separately, their combined use was superior and, in some models, was the only effective approach; this was evident when the β-blocker propranolol was combined with the semiselective COX2 synthesisinhibitor etodolac. 95,96 Our ability to draw definitive conclusions based on the aforementioned retrospective studies is limited by 1) the heterogeneity of the drugs used, 2) the types of cancer and cancer stages, 3) different definitions of the perioperative period, 4) the fact that retrospective studies rely on data for patients with various comorbidities, 14 Although inconclusive, evidence seems to suggest an advantage for nonselective β-blockers (eg, propranolol) 94,99,100 and for both COX1 and COX2 blockade (eg, through the semiselective COX2 inhibitor etodolac). Perioperative COX inhibition also has provided inconclusive results, as recently reviewed by Cata et al 43 Notably, aspirin, a nonselective COX inhibitor, was recently recommended for the prevention of colorectal cancer (CRC) in men at risk between the ages of 50 and 59 years.…”

“…16,43 Specifically, 2 RCTs using celecoxib (a selective COX2 inhibitor; n = 32) 102 and low-dose aspirin (n = 40), 95 respectively, showed a slight reduction of systemic inflammatory markers (PG metabolites in urine) during cancer surgery and reduced PGE2 levels in the rectal mucosa of patients undergoing CRC screening. 16,43 Specifically, 2 RCTs using celecoxib (a selective COX2 inhibitor; n = 32) 102 and low-dose aspirin (n = 40), 95 respectively, showed a slight reduction of systemic inflammatory markers (PG metabolites in urine) during cancer surgery and reduced PGE2 levels in the rectal mucosa of patients undergoing CRC screening.…”

“…Perioperative COX inhibition also has provided inconclusive results, as recently reviewed by Cata et al 43 Notably, aspirin, a nonselective COX inhibitor, was recently recommended for the prevention of colorectal cancer (CRC) in men at risk between the ages of 50 and 59 years. 95,96 Our ability to draw definitive conclusions based on the aforementioned retrospective studies is limited by 1) the heterogeneity of the drugs used, 2) the types of cancer and cancer stages, 3) different definitions of the perioperative period, 4) the fact that retrospective studies rely on data for patients with various comorbidities, 14,16,17,97 and 5) an immortal time bias (a bias from the inclusion of treated patients who survived postoperatively before taking medication; see Weberpals et al 97 and Suissa 98 ).…”

“…Several perioperative randomized controlled trials (RCTs) are ongoing, and a few have already provided initial promising results regarding the effects of the inhibition of either CAs or COX signaling on cancer outcomes and on indices of inflammation and immunity. 16,43 Specifically, 2 RCTs using celecoxib (a selective COX2 inhibitor; n = 32) 102 and low-dose aspirin (n = 40), 95 respectively, showed a slight reduction of systemic inflammatory markers (PG metabolites in urine) during cancer surgery and reduced PGE2 levels in the rectal mucosa of patients undergoing CRC screening.…”