Chemoprevention of colon and small intestinal tumorigenesis in APC(Min/+) 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), such as 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 {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid}, in APC(Min/+) mouse intestinal tumorigenesis. Six-week-old male and female APC(Min/+) mice (n = 10 per group) were fed with control American Institute of Nutrition-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 more than 83% (P < 0.0001) tumor inhibition in both genders of mice. One hundred and fifty and 300 ppm licofelone resulted in 86% to 97% inhibition of polyps having size greater than 2 mm. One hundred and fifty and 300 ppm licofelone caused more than 72% and 100% inhibition of colonic tumors, respectively. Importantly, in mice fed with licofelone, tumors showed significantly reduced proliferating cell nuclear antigen expression (70%, P < 0.0001), increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells (75%, P < 0.0001), and there was dose-dependent suppression of serum triglycerides (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 show that a novel dual 5-LOX/COX inhibitor dramatically suppresses small intestinal and colonic tumor formation in APC(Min/+) mice.

• Authors: Altaf Mohammed, Naveena B Janakiram, Qian Li, Chang-In Choi, Yuting Zhang, Vernon E Steele, Chinthalapally V Rao
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 4 Issue 12 Pg. 2015-26 (Dec 2011) ISSN: 1940-6215 [Electronic] United States
• PMID: 21885812 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: 2011 AACR

Chemical References

• Adenomatous Polyposis Coli Protein
• Cyclooxygenase Inhibitors
• Pyrroles
• RNA, Messenger
• Arachidonate 5-Lipoxygenase
• Cyclooxygenase 2
• licofelone

Topics

• Adenomatous Polyposis Coli Protein (physiology)
• Animals
• Apoptosis (drug effects)
• Arachidonate 5-Lipoxygenase (chemistry, genetics, metabolism)
• Blotting, Western
• Cell Proliferation (drug effects)
• Colonic Neoplasms (enzymology, pathology, prevention & control)
• Cyclooxygenase 2 (chemistry, genetics, metabolism)
• Cyclooxygenase Inhibitors (therapeutic use)
• Female
• Humans
• Intestinal Neoplasms (enzymology, pathology, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Pyrroles (therapeutic use)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction