title: 5MeCDDO Blocks Metabolic Activation but not Progression of Breast, Intestine, and Tongue Cancers. Is Antioxidant Response Element a Prevention Target?
abstract: The preventive efficacy of the triterpenoid 5MeCDDO was tested in two models of mammary cancer, the Min model of intestinal cancer, and a chemically induced model of head and neck cancer. In one model of mammary cancer, female Sprague-Dawley rats were administered MNU at 50 days of age, and 5MeCDDO (27 ppm) was administered in the diet beginning 5 days later for the duration of the study; 5MeCDDO was ineffective. In contrast, in a model examining initiation of mammary cancers by the procarcinogen dimethyl-benzanthracene, 5, 6-benzoflavone (500 ppm, an Ah receptor agonist) or 5MeCDDO (27 or 2.7 ppm) decreased tumor multiplicity by 90%, 80%, and 50%, respectively. This anti-initiating effect which is presumably mediated by altered metabolic activation parallels our observation that 5MeCDDO induced proteins of various antioxidant response element (ARE)-related phase II drug-metabolizing enzymes [e.g., GST Pi, AKR 7A3 (aflatoxicol), epoxide hydrolase, and quinone reductase] in the liver. 5MeCDDO tested in the 4-nitroquinoline-l-oxide (4-NQO) head and neck cancer model failed to decrease tumor incidence or invasiveness. In the Min mouse model of intestinal cancer, a high dose of 5MeCDDO (80 ppm) was weakly effective in reducing adenoma multiplicity [∼30% (P < 0.05)]; however, a lower dose was totally ineffective. These findings question whether measuring increased levels of certain ARE-related genes (e.g., quinone reductase, GST Pi), indicating decreased carcinogen activation are sufficient to imply general chemopreventive efficacy of a given agent or mixture. Cancer Prev Res; 9(7); 616-23. ©2016 AACR.
authors.affiliation: Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, Maryland.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.affiliation: Department of Cell Biology & Physiology and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Reid
authors.initials: R
authors.lastname: Townsend
authors.affiliation: Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Margie L
authors.initials: ML
authors.lastname: Clapper
authors.affiliation: Chemoprevention Center, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: M Margaret
authors.initials: MM
authors.lastname: Juliana
authors.affiliation: Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, Maryland.
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.affiliation: Life Sciences Group, IIT Research Institute, Chicago, Illinois.
authors.forename: David L
authors.initials: DL
authors.lastname: McCormick
authors.affiliation: Chemoprevention Center, University of Alabama at Birmingham, Birmingham, Alabama. clintongrubbs@uabmc.edu.
authors.forename: Clinton J
authors.initials: CJ
authors.lastname: Grubbs
mesh_terms: D065767:Activation, Metabolic / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D061745:Antioxidant Response Elements / Q000187:drug effects*; D002273:Carcinogens / Q000633:toxicity; D018450:Disease Progression; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007414:Intestinal Neoplasms / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008806:Mice, Inbred AKR; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014062:Tongue Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D000970:Antineoplastic Agents; D002273:Carcinogens; D007093:Imidazoles; D009828:Oleanolic Acid