Abstract 5244: Effects of chronic low dose aspirin treatment in the mouse AOM/DSS model of colon carcinogenesis

Abstract

Abstract Although early detection and treatment of colorectal cancer (CRC) have improved in recent years, it remains a significant healthcare problem with high morbidity and mortality. Published data indicate that long-term intake of low dose aspirin reduces the risk of CRC, however the molecular mechanisms underlying this effect are still unclear. The aim of this study was to investigate the efficacy of low dose equivalent aspirin treatment in a mouse colon carcinogenesis model, including evaluation of potential mechanistic contributors. An initial PK/PD study in healthy mice indicated that aspirin 25 mg/kg/day given via drinking water had a similar PD effect - reduction in plasma thromboxane B2 (TXB2), as an indicator of cyclooxygenase-1 (COX-1) inhibition - as did 5-day low-dose aspirin treatment (100 mg/day) in healthy human volunteers. Male and female C57BL/6J mice were treated with the carcinogen azoxymethane (AOM) 10 mg/kg once i.p. combined with three 5-day cycles (at 14 day intervals) of dextran sodium sulphate (DSS) 2% in drinking water. Aspirin treatment was started concomitant with AOM administration and continued for 12 weeks, at which time the data outlined below were obtained. Aspirin 25 mg/kg/day significantly reduced tumor burden in 3 independent experiments (total tumor number reduced by 43 - 51%; tumor area per mouse reduced by 59 - 65%; mean tumor area reduced by 22 - 27%). Increasing the dose to 50 mg/kg/day did not show better inhibition of tumorigenesis. Aspirin-induced reduction in tumorigenesis in this model was accompanied by reduction in systemic plasma TXB2 by about 70%, indicating reduced platelet activation. TXB2 production by colon explants was also reduced, by 30-50%. Aspirin treatment reduced inflammatory activity (fecal blood; IL-1β and IL-6 production by colon explant cultures; iNOS-positive tumor macrophage infiltration). Immunohistological analysis of tumor tissue showed no reduction in proliferation (BrdU staining) by aspirin but there was a trend towards increased apoptosis (caspase-3 positive cells) and a significant reduction in CD31-positive microvessel density. Aspirin treatment did not result in significant modulation of the Wnt/β-catenin, NF-κB or HIF-1 pathways as assessed by mRNA expression of several of their target genes in tumor tissue. The results show that aspirin can inhibit tumor development in this established model of colon carcinogenesis, primarily by reducing tumor number with a less marked effect on the size of individual tumors. This effect is associated with COX-1 inhibition of a similar magnitude to that seen with low dose aspirin in humans. The influence of aspirin on intestinal inflammation and platelet activation as well as on tumor cell apoptosis and tumor angiogenesis might all contribute to the beneficial effects seen in this model. Additional studies are planned to further elucidate aspirin's mechanism of action in inhibiting tumor development. Citation Format: Nadine Rohwer, Anja Kuehl, Dieter Zopf, Fiona M. McDonald, Karsten-Heinrich Weylandt. Effects of chronic low dose aspirin treatment in the mouse AOM/DSS model of colon carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5244.