Chemoprevention of Colon and Small Intestinal Tumorigenesis in APCMin/+ mice by Licofelone A Novel Dual 5-LOX/COX Inhibitor: Potential Implications for Human Colon Cancer Prevention

摘要

Preclinical and clinical studies suggest that 5-lipoxygenase (5-LOX), like cyclo-oxygenase-2 (COX-2), is a potential target for colon cancer inhibition and, in part, contributes to cardiovascular side effects associated with COX-2 inhibitors. Experiments were designed to assess the chemopreventive effects of a novel dual 5-LOX/COX inhibitor, Licofelone, in APC^Min/+ mouse intestinal tumorigenesis. Six week-old male and female APC^Min/+ mice (n=10 per group) were fed control AIN-76A diet or diets containing 150 or 300 ppm licofelone for 14 weeks (~100 days), and intestinal tumors were evaluated for tumor multiplicity and size. Licofelone significantly inhibited total intestinal tumor multiplicity and size in a dose-dependent manner (p<0.0001; mean tumors for 0, 150 and 300 ppm: 48.8, 17, and 8, respectively, in male mice; and 34.3, 8.8, and 5.5, respectively, in female mice). Licofelone at high-dose showed >83% (p<0.0001) tumor inhibition in both genders of mice. 150 and 300 ppm licofelone resulted 86%–97% inhibition of polyps>2-mm. 150 and 300 ppm licofelone caused >72% and 100% inhibition of colonic tumors, respectively. Importantly, in mice fed licofelone, tumors showed significantly reduced PCNA expression (70%, P<0.0001), increased TUNEL positive cells (75%, p<0.0001), and there was dose-dependent suppression of serum triglycerids (71–83%, p<0.0001), decreased inflammatory cytokines; and decreased COX and 5-LOX activities (57–64%, p<0.0001). Also, compared with 300 ppm celecoxib, 300 ppm licofelone provided better efficacy in suppressing tumor growth. These observations demonstrate that a novel dual 5-LOX/COX inhibitor dramatically suppresses small intestinal and colonic tumor formation in APC^Min/+ mice.