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 five days later for the duration of the study; 5MeCDDO was ineffective. In contrast, in a model examining initiation of mammary cancers by the pro-carcinogen dimethyl-benzanthracene (DMBA), 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 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 [approximately 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.

Comparison of Effects of Diet on Mammary Cancer: Efficacy of Various Preventive Agents and Metabolomic Changes of Different Diets and Agents

“…7,8). We have also reported on a variety of agents that are ineffective preventive agents in this model including metformin, statins, antioxidant response element (ARE) agonists, and NSAIDs (9)(10)(11).…”

“…Treatment of female Sprague-Dawley rats was done as described previously (6,10). In brief, rats were obtained from Envigo, Inc. and were housed in Institutional Animal Care and Use Committee (IACUC)-approved animal facilities at the University of Alabama at Birmingham (Birmingham, AL) beginning at 35 DOA.…”

“…Statistical analyses of cancer incidence and latency were determined using log-rank analysis. Differences in cancer multiplicity were determined by the Armitage test, and differences in final tumor weights were determined by Wilcoxon rank test (7,10).…”

Pharmacometabolomic Pathway Response of Effective Anticancer Agents on Different Diets in Rats with Induced Mammary Tumors

“…Chemoprevention studies . Treatment of female Sprague–Dawley rats was conducted as described previously [3,14]. In brief, rats (obtained from Envigo, Inc., Huntingdon, CBG, UK) were housed in Institutional Animal Care and Use Committee (IACUC)-approved animal facilities at the University of Alabama at Birmingham (Birmingham, AL, USA) beginning at 35 days of age (DOA).…”

Screening of Chemopreventive Agents in Animal Models: Results on Reproducibility, Agents of a Given Class, and Agents Tested During Tumor Progression

“…The reason several of these compounds were tested initially was a specific clinical interest in these agents (based on epidemiologic studies or published preclinical data) which encouraged their examination. The four agents/classes to be discussed are statins, metformin, NSAIDs, and ARE agonists (25,26,27,28). It was felt that negative results with these agents were likely to prove controversial, particularly with statins and metformin.…”