title: 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: Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors: Altaf
authors: A
authors: Mohammed
authors: Naveena B
authors: NB
authors: Janakiram
authors: Qian
authors: Q
authors: Li
authors: Chang-In
authors: CI
authors: Choi
authors: Yuting
authors: Y
authors: Zhang
authors: Vernon E
authors: VE
authors: Steele
authors: Chinthalapally V
authors: CV
authors: Rao
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007414:Intestinal Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011758:Pyrroles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D016861:Cyclooxygenase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C088092:licofelone