Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis

Abstract

Meta-analyses have demonstrated that low dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the anti-platelet action of low dose aspirin likely contributes to its anti-metastatic effect. Cycloxooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) also contributes to metastasis, and we addressed the hypothesis that low dose aspirin also inhibits PGE2 biosynthesis. We show that low dose aspirin inhibits systemic PGE2 biosynthesis by 45% in healthy volunteers (p <0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells up-regulates COX-2 expression and PGE2 biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE2 production by the platelet-tumor cell aggregates. In conclusion, low dose aspirin has a significant effect on extraplatelet cyclooxygenase, and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE2 biosynthesis in metastasizing tumor cells.

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

“…Low‐dose aspirin was more effective in acetylating COX‐1 in blood platelets than in colorectal mucosa, despite inhibiting COX‐1 activity with comparable potency in intestinal epithelial cells and platelets in vitro (refs. , and the present study). The exposure of platelets to a higher concentration of intact ASA in the presystemic circulation is a plausible determinant of the higher extent of acetylation of COX‐1 in platelets than colorectal mucosa demonstrated in the present study.…”

“…These assessments were secondary endpoints and the statistical power of the clinical study was inadequate to detect moderate treatment effects. Recently, Boutaud et al . reported that low‐dose aspirin reduced urinary PGE‐M and PGI‐M levels by 45% and 37%, respectively, in a larger population of healthy subjects.…”

Molecular Pathways: Targeting the Microenvironment of Liver Metastases

“…In fact, there is already proof of principle, albeit unappreciated, for the utility of this concept because an effective “chemoprevention” strategy for CRCLM already exists, namely the use of low dose aspirin. Aspirin (ASA), a negative regulator of prostaglandin E2 signaling via its inhibitory effects on the COX1 and 2 enzymes has now been shown to significantly reduce CRCLM in several epidemiological studies (67). While not completely understood, it is believed that the mechanism of action (MOA) relates to the effect of ASA on COX1 signaling in platelets (68).…”

“…While not completely understood, it is believed that the mechanism of action (MOA) relates to the effect of ASA on COX1 signaling in platelets (68). In the microvascular phase of LM, platelets may promote metastases by enhancing cancer cell adhesion to EC and leukocytes, thereby facilitating transmigration (67). Platelets may also aid in the evasion of NK surveillance.…”

Effect of photodynamic therapy combined with Celecoxib on expression of cyclooxygenase-2 protein in HeLa cells

“…Phospholipids in the cell membrane are rich in arachidonic acid so when the cells are stimulated by external stimuli, including bradykinin, thrombin, antigen-antibody complexes or other pathological factors, a number of which have not yet been characterized, the phospholipase A2 in cell membrane will be activated, consequently hydrolyzing the phospholipids and releasing arachidonic acid, which may then synthesize PGs under a series of enzymes including COX-2 and PGs synthetase (20). In the majority of normal tissues, PG is not expressed; however, under the stimuli of factors such as cytokines, growth factors, oncogenes or tumor-promoting agents, it may be upregulated and associated with the occurrence and development of tumors (21). Previous study has identified that COX-2 is upregulated in a number of tumor tissues and is associated with tumorigenesis, malignant transformation, resistance or prognosis (22).…”