Effects of chronic low‐dose aspirin treatment on tumor prevention in three mouse models of intestinal tumorigenesis

Abstract

Although early detection and treatment of colorectal cancer (CRC) have improved, it remains a significant health‐care problem with high morbidity and mortality. Data indicate that long‐term intake of low‐dose aspirin reduces the risk of CRC; however, the mechanisms underlying this chemopreventive effect are still unclear. Different mouse models for inflammation‐associated, sporadic, and hereditary CRC were applied to assess the efficacy and mechanism of low‐dose aspirin on tumor prevention. An initial dosing study performed in healthy mice indicates that aspirin at a dose of 25 mg/kg/d has a similar pharmacodynamic effect as low‐dose aspirin treatment in human subjects (100 mg/d). Chronic low‐dose aspirin treatment suppresses colitis‐associated and to a lesser extent spontaneous tumorigenesis in mice. Aspirin's antitumor effect is most pronounced in a preventive approach when aspirin administration starts before the tumor‐initiating genotoxic event and continues for the duration of the experiment. These effects are not associated with alterations in cell proliferation, apoptosis, or activation of signaling pathways involved in CRC. Aspirin‐induced reduction in tumor burden is accompanied by inhibition of thromboxane B2 formation, indicating reduced platelet activation. Aspirin treatment also results in decreased colonic prostaglandin E2 formation and tumor angiogenesis. With respect to colitis‐triggered tumorigenesis, aspirin administration is associated with a reduction in inflammatory activity in the colon, as indicated by decreased levels of pro‐inflammatory mediators, and tumor‐associated iNOS‐positive macrophages. Our results suggest that low‐dose aspirin represents an effective antitumor agent in the context of colon tumorigenesis primarily due to its well‐established cyclooxygenase inhibition effects.

Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid

“…Aspirin dosing in our CD1 Nude mouse model [ 36 , 37 ], which mimicked low-dose aspirin use in humans, based on profound platelet COX-1 inhibition but an absence of systemic COX-2 inhibition, did not increase the sensitivity of MC38 mouse CRC cell tumours to EPA in vivo, in direct contrast to the corresponding in vitro data. We demonstrated that there was inefficient inhibition of PGE 2 production in CRC cell tumour tissue, despite efficient systemic COX-1 inhibition.…”

Combined Targeted Proteomics and Oxylipin Metabolomics for Monitoring of the COX‐2 Pathway

“…The developed targeted proteomics method was applied to characterize COX‐2 abundance in parallel to COX activity in three human colon carcinoma cell lines HCT‐116, HT‐29, and HCA‐7. Because of the central role of COX‐2 in colorectal cancer [ 7,47 ] it is interesting to study the ARA cascade in these cells producing different levels of prostanoids (Figure 3Ai,ii; Table S7, Supporting Information). Among the investigated compounds (ARA‐derived prostanoids), PGE 2 and 12‐HHT showed the highest levels and were detectable in all cell lines and may therefore serve as indicators of COX activity.…”

“…[ 5 ] Although constitutive COX‐2 (derived from the PTGS2 gene) expression is found in few tissues (e.g., brain), its expression is mainly regulated by growth factors, cytokines (such as tumor necrosis factor α or interleukin 1β) and pro‐inflammatory stimuli, for example, through the NFκb‐pathway. [ 6 ] Elevated COX‐2 gene expression has been reported in colon and several other cancers [ 7,8 ] as well as during diseases that are accompanied by chronic inflammation such as atherosclerosis. [ 9 ] This central role of COX‐2 in the mediation of inflammatory responses has made it a major target for drug development in the past years.…”

Short-Chain Fatty Acids: A Soldier Fighting Against Inflammation and Protecting From Tumorigenesis in People With Diabetes

“…As an inhibitor of cyclooxygenase (COX)-1, aspirin exerts its significant chemo-preventive effects in CRC through inhibition of NF-κB dependent pathways, Wnt/β-catenin signaling, and additional COX proteins acetylation ( 150 , 151 ). The notable anti-tumor effects of aspirin have been observed by reduction in platelet activation, inhibition of tumor angiogenesis, and decrease of pro-inflammatory agents ( 152 ). In addition, low-dose aspirin could reduce metastasis in colon cancer, mainly due to its effective inhibition of prostaglandin E2 (PGE2) formation and platelet-tumor cell aggregation ( 153 ).…”