title: Multitargeted low-dose GLAD combination chemoprevention: a novel and promising approach to combat colon carcinogenesis.
abstract: Preclinical studies have shown that gefitinib, licofelone, atorvastatin, and α-difluoromethylornithine (GLAD) are promising colon cancer chemopreventive agents. Because low-dose combination regimens can offer potential additive or synergistic effects without toxicity, GLAD combination was tested for toxicity and chemopreventive efficacy for suppression of intestinal tumorigenesis in adenomatous polyposis coli (APC)(Min/+) mice. Six-week-old wild-type and APC(Min/+) mice were fed modified American Institute of Nutrition 76A diets with or without GLAD (25 + 50 + 50 + 500 ppm) for 14 weeks. Dietary GLAD caused no signs of toxicity based on organ pathology and liver enzyme profiles. GLAD feeding strongly inhibited (80-83%, P < .0001) total intestinal tumor multiplicity and size in APC(Min/+) mice (means ± SEM tumors for control vs GLAD were 67.1 ± 5.4 vs. 11.3 ± 1.1 in males and 72.3 ± 8.9 vs 14.5 ± 2.8 in females). Mice fed GLAD had >95% fewer polyps with sizes of >2 mm compared with control mice and showed 75% and 85% inhibition of colonic tumors in males and females, respectively. Molecular analyses of polyps suggested that GLAD exerts efficacy by inhibiting cell proliferation, inducing apoptosis, decreasing β-catenin and caveolin-1 levels, increasing caspase-3 cleavage and p21, and modulating expression profile of inflammatory cytokines. These observations demonstrate that GLAD, a novel cocktail of chemopreventive agents at very low doses, suppresses intestinal tumorigenesis in APC(Min/+) mice with no toxicity. This novel strategy to prevent colorectal cancer is an important step in developing agents with high efficacy without unwanted side effects.
authors: Center for Cancer Prevention and Drug Development, Hematology-Oncology Section, Department of Medicine, PC Stephenson Cancer Center, 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: Misty
authors: M
authors: Brewer
authors: Krishna
authors: K
authors: Vedala
authors: Vernon E
authors: VE
authors: Steele
authors: Chinthalapally V
authors: CV
authors: Rao
mesh_terms: D018256:Adenomatous Polyps / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069059:Atorvastatin; D063646:Carcinogenesis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D000518:Eflornithine / Q000008:administration & dosage; D005260:Female; D000077156:Gefitinib; D006538:Heptanoic Acids / Q000008:administration & dosage; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D011758:Pyrroles / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage
chemical_list: D016207:Cytokines; D006538:Heptanoic Acids; D011758:Pyrroles; D011799:Quinazolines; D000069059:Atorvastatin; C088092:licofelone; D000077156:Gefitinib; D000518:Eflornithine
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