Abstract 827: The protective effects of the synthetic triterpenoid CDDO-methyl ester on colitis associated colon cancer

Abstract

Abstract Colitis-associated colon cancer (CAC) is the principal colorectal cancer associated with inflammatory bowel disease, and is associated with a high mortality rate. The synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-C28-methyl ester (CDDO-me) has been shown to exert potent anti-inflammatory effects, and to suppress the growth and inhibit viability of colon cancer cells. However, the utility of triterpenoids in the chemoprevention of CAC has not been investigated. Therefore, we have interrogated the ability of CDDO-me to suppress inflammation and epithelial transformation in a unique mouse model of colon cancer developed in our laboratory, in which a T cell-restricted disruption of the Smad4 gene leads to progressive inflammation and epithelial neoplasia. Smad4 is a common intermediate in the signaling pathways for transforming growth factor-beta (TGF-β), bone morphogenetic protein (BMP), Activin and other members of the TGF-β superfamily. Naïve Smad4−/− T cells are develop a pro-inflammatory phenotype characterized by the production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IFN-γ) and are unable to differentiate to a suppressor T cell phenotype in response to TGF-beta. Mice lacking T cell expression of Smad4 (Smad4co/coTcellCre+) exhibit progressive mucosal inflammation and thickening, including increased expression of inflammatory mediators (iNOS, COX-2), and a concomitant loss of expression of important tumor suppressors, including 15-hydroxyprostaglandin dehydrogenase (15-PGDH), compared to wild type littermates. Treatment of Smad4co/coTcellCre+ mice with CDDO-me for 1 month significantly reduces the inflammation, weight loss, and epithelial neoplasia. These effects were also associated with an overall increase in survival in CDDO-me treated Smad4co/coTcellCre+ mice compared with those receiving vehicle alone. CDDO-me treatment down regulated the production of pro-inflammatory cytokines and the expression of iNOS and COX-2 in the colon epithelium and restored the expression of 15-PGDH. We investigated the direct effects of CDDO-me on colon epithelial cells using FET cells and found that CDDO-me induced 15-PGDH transcripts and protein expression in a dose dependent manner. Finally, CDDO-me activated TGF-β signaling and potentiated TGF-β induced 15-PGDH expression in a manner that could be blocked by TGF-β signaling inhibitors. This in vivo induction of 15-PGDH expression was not observed in mice with a germ-line deletion of the gene encoding the TGF-β intermediate, Smad3. These data suggest that CDDO-me increases the expression of 15-PGDH by potentiating TGF-β signaling in colon epithelial cells. Therefore, CDDO-me may be a potent agent for the chemoprevention of colitis induced colon cancer due to its ability to increase the expression of 15-PGDH and down-regulate the expression of pro-inflammatory mediators. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 827. doi:10.1158/1538-7445.AM2011-827