Piroxicam promotes apoptosis and has a twofold effect on colon tumorigenesis in Mlh1/Apc mouse

Abstract

1026 Background: Increase amount of cyclooxygenase 2 (COX-2) is commonly found in malignant and premalignant lesions and overexpression of COX-2 is associated with both human and animal colon cancer. It has recently become evident that nonsteroidal anti-inflammatory drugs (NSAIDs) such as piroxicam, which inhibits the constitutive (COX-1) and inducible (COX-2) isoforms, represent a potential class of cancer chemopreventive agents. The mechanism of action of piroxicam on gastrointestinal cancer has not been determined. The present study examines the effect of piroxicam on Mlh1/APC 1638N mice, a preclinical model of intestinal cancer. Methods: Mice were fed orally once daily for 9 weeks with either AIN-76 diet or the same diet supplemented with piroxicam (60 ppm). Upon completion of treatment, the number and location of intestinal tumors was determined. Additional variables examined were the mean number of apoptotic cells in each crypt in the cecum and in the small intestine. Results: Administration of piroxicam to Mlh1/Apc mice produced an 82% decrease of the mean number of tumor per mouse in the small intestine (0.09 vs 0.5 respectively, p<0.05) and an increase in the cecum (1.18 vs 0.1, p<0.01) compared to vehicle-treated mice. The number of apoptotic positive cells/crypt was increased in the small intestine (0.21 versus 0.87, p<0.05) but also in the cecum (0.35 versus 0.84, p < 0.001). In small intestine, however, apoptosis was mostly triggered at the base of the crypt, the area considered to harbour the stem cells, whilst a whole length crypt apoptotic activation was found in the cecum. Conclusions: Piroxicam was able to induce apoptosis in intestinal mucosa, to reduce tumor number in the small intestine, and to increase tumorigenesis in the cecum when administered to Mlh1/Apc mice. Differences in the intramucosa distribution of the piroxicam-induced apoptosis between the two locations could be responsible for differences in tumor response. The findings in the present study call in to question the utility of piroxicam as a stand-alone chemopreventive agent. No significant financial relationships to disclose.