Abstract 4678: Unexpected lack of activity of Bardoxolone (5MeCDDO) in progression period of rodent models of breast, intestinal and head and neck cancers. What does it mean for the ARE as a primary prevention target.
Authors: Lubet Ronald A. , Clapper Margie , Townsend Reid , MCcormick David , Grubbs Clinton 
Published: August 2014

The preventive efficacy of the triterpenoid 5MeCDDO was evaluated in multiple preclinical models of cancer. This included three models of breast cancer, the Min mouse model of intestinal cancer, and the 4-nitroquinoline-1-oxide (4NQO) induced model of head and neck cancer. In the ER+ model of breast cancer, Sprague Dawley rats were administered MNU, i.v., at 50 days of age and 5MeCDDO (27 ppm) was administered in the diet beginning 5 days post MNU for the duration of the study. 5MeCDDO failed to alter tumor latency or multiplicity and, in fact, increased the size of the tumors which did occur. This concentration of 5MeCDDO increased liver to body weight ratios. 5MeCDDO was also examined in a transgenic model (MMTV Neu /P53KO) in which mice develop ER negative cancers; which over-express Neu and have a P53 alteration. Similarly to results in the MNU model, the compound failed to alter either tumor latency or multiplicity. The effect of 5MeCDDO was then examined in an additional mammary model in which ER+ tumors are induced by the procarcinogen dimethylbenzanthracene (DMBA). In this model, which examines the ability of an agent to alter the activation of DMBA, the preventive agent was administered beginning 7 days prior to DMBA and continued 7 days post DMBA. 5,6 Benzoflavone (500 ppm), a positive control, decreased tumor multiplicity &gt;90%, while 5MeCDDO (27 or 2.7 ppm) decreased multiplicity 65 and 35%, respectively. The efficacy observed in this cancer initiation model fits with our finding that 5MeCDDO induces a variety of ARE related Phase II drug-metabolizing genes; e.g., GST Pi, AKR 7A3 (aflatoxicol) epoxide hydrolase, and quinone reductase as determined by proteomic analysis. As expected, high induction of the ARE response element and associated genes yielded decreases in carcinogen-induced tumor initiation. Additionally, we examined the effects of 5MeCDDO on the development of intestinal adenomas in Min mice and head and neck tumors. In the 4NQO treated rats, 5MeCDDO failed to decrease the progression stages of development. In the Min model, a high dose of 5MeCDDO (80 ppm) was weakly effective, reducing adenoma multiplicity roughly 30% (P&lt;0.01); however, a lower dose was totally ineffective. These findings brings into question whether merely measuring induction of the genes associated with the ARE response (e.g., quinone reductase, GST Pi or AKR 7A3) is sufficient to imply the general preventive efficacy of a given agent or mixture. That is, 5MeCDDO highly activated the ARE response, but was inactive in various prevention models.

Citation Format: Ronald A. Lubet, Margie Clapper, Reid Townsend, David MCcormick, Clinton Grubbs. Unexpected lack of activity of Bardoxolone (5MeCDDO) in progression period of rodent models of breast, intestinal and head and neck cancers. What does it mean for the ARE as a primary prevention target. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4678. doi:10.1158/1538-7445.AM2013-4678