Sulindac and a cyclooxygenase-2 inhibitor, etodolac, increase APC mRNA in the colon of rats treated with azoxymethane

Abstract

Background-Non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to protect against the development of colon cancer. However, the mechanism(s) by which NSAIDs exert their eVects is not clear. Aims-The aim of this study was to examine the eVects of NSAIDs on mRNA expression of tumour suppressor adenomatous polyposis coli (APC) gene in rat colon mucosa. Methods-Starting at six weeks of age, three groups of rats (groups 1, 2, and 3) were treated with azoxymethane (AOM), a colon specific carcinogen, and another three groups (groups 4, 5, and 6) were not given AOM. Groups 2 and 3 were given 10 mg/kg of sulindac or etodolac, respectively, three times weekly during the experiment. Groups 4 and 5 were also given sulindac or etodolac, respectively, in the same manner as in groups 2 and 3. Group 6 (untreated control) was not given any agent (AOM or NSAIDs). At 10 weeks of age, preneoplastic lesions (aberrant crypt foci (ACF)) induced by AOM in the colon were counted, and the level of expression of APC mRNA in the colonic mucosa was estimated by the reverse transcription-competitive polymerase chain reaction method and northern blot analysis. Results-Mean occurrence of ACF in rats in groups 2 and 3 was reduced to approximately 50% of that in group 1. The level of APC mRNA expression in group 1 (AOM alone) was lower than that in group 6 (untreated control) (p<0.05); however, levels of APC mRNA expression in groups 2, 3, 4, and 5, to which NSAIDs had been administered, were significantly increased compared with levels in groups 1 and 6 (p<0.01). Conclusions-Both sulindac and etodolac reduced the occurrence of ACF and induced an increase in APC mRNA in rat colon mucosa.

Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A

“…Evidence has been building that there may be direct effects of NSAIDs on this pathway (Kishimoto et al, 2000;Smith et al, 2000;Dihlmann et al, 2001). This would concur with the epidemiological data that suggest NSAIDs act at a very early stage in colon cancer and must be given at this earliest point in the disease process to be effective (Giovannucci et al, 1995).…”

The Chemopreventive Agent Sulindac Attenuates Expression of the Antiapoptotic Protein Survivin in Colorectal Carcinoma Cells

“…One possible mechanism is that sulindac increases expression of APC (Schnitzler et al, 1996;Kishimoto et al, 2000) and that APC decreases survivin expression because, as we have shown (Zhang et al, 2001), APC downregulates survivin through the ␤-catenin:Tcf-4 pathway. However, HT-29 cells lack wild-type APC, which excludes this possibility.…”

Celecoxib Treatment Alters the Gene Expression Profile of Normal Colonic Mucosa

“…ACFs are considered to be an early preneoplastic lesion in the colon (75), and the ability to decrease the frequency of ACF after carcinogen treatment is used routinely in experimental models of colon cancer to estimate the cancer preventive effect of different agents (76). It is particularly well established that NSAIDs (77)(78)(79) and celecoxib (80)(81)(82)(83) decrease the frequency of carcinogen-induced ACFs in the colon in animal models. It has also been shown that the number of ACF in patients who received sulindac sulfide is decreased (84).…”