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

Abstract

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 APCMin/+ mouse intestinal tumorigenesis. Six week-old male and female APCMin/+ 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 APCMin/+ mice.

Role of arachidonic acid metabolites on the control of non-differentiated intestinal epithelial cell growth

“…Although the translation of an in vitro Caco-2 cell data into in vivo situation necessitates further investigation using colorectal cancer models, this study proposes that HETEs produced by LOXs together COX metabolites might be important elements involved in the control of intestinal epithelial cell growth. Findings in agreement with Cianchi et al (2006) who reported that 5-LOX inhibitors could augment the antitumor activity of COX inhibitor; and with Mohammed et al (2011) who observed that dual 5-LOX/COX inhibitor dramatically suppresses colonic tumor formation.…”

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

“…Mice were infected with adeno-Cre and transferred to a tamoxifen-containing diet, as in the earlier experiments. Two weeks following the addition of tamoxifen, mice were treated with either vehicle or licofelone-a dual COX/5-LOX pathway inhibitor, which has shown promising chemopreventive efficacy in lung and colon cancers (34,35). Remarkably, after only four doses we found substantially reduced tumor load when compared with vehicletreated controls (Fig.…”

Role of lipoxins, resolvins, and other bioactive lipids in colon and pancreatic cancer

“…Targeting both COX-2 and 5-LOX pathways may be a more effective and safer approach for cancer chemoprevention. Recently, we have shown chemopreventive effects of the dual COX/5-LOX inhibitor, licofelone in colon and pancreatic cancer models [55,56]. Long-term safety profiles of dual COX/5LOX inhibitors are not a major concern for cancer chemoprevention since these agents already were tested in phase III clinical trial for osteoporosis and found to be safe and effective [51,57].…”