Abstract LB-266: Suppression of colitis-associated colon carcinogenesis by the natural triterpenoid celastrol

Abstract

Abstract Celastrol is a natural triterpenoid isolated from the medicinal herb Triptyrgium wilfordii, commonly known as the Thunder of God vine. Celastrol has been shown to have a broad range of anti-inflammatory and anti-cancer activities. Here we investigated whether celastrol administered as a dietary supplement can inhibit both colitis and colitis-associated colon cancer (CAC) in either genetic or chemically-induced CAC mouse models. As a genetic and spontaneous, inflammatory-driven intestinal neoplasia model, we generated a Smad4TKO / p27Kip1-/- (DKO) mouse in which a germ line p27Kip1 gene deletion (p27Kip1-/-) was combined with the T cell-restricted deletion of the Smad4 gene (Smad4TKO). All DKO mice developed spontaneous gastrointestinal inflammation and colon carcinoma by 3 months of age. Administration of celastrol as a dietary supplement (2 mg/day) to DKO mice increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators, including TNF-alpha, IL-6, IL-1beta and iNOS. We investigated the chemopreventive activity of celastrol in the chemically induced CAC mouse model using dextran sulfate sodium (DSS)/azoxymethane (AOM). Mice (C57/BL6, ages 6-8 weeks) received intraperitoneal injections with 10 mg/kg AOM, followed by exposure to 2% DSS in drinking water for 7 days. We repeated 3 cycles of 2% DSS, with 10 days of normal drinking water provided between cycles. Mice were either maintained on control diet or given celastrol (2 mg/day) diet beginning with first administration of DSS and continuing until termination of the experiment. Mice receiving celastrol diet showed less loss in body weight compared with the control diet group and marked protection from AOM/DSS-induced colon cancer. The incidence and number of colonic tumors in mice in the celastrol diet group were also significantly lower than those in control diet group. These results were accompanied by decreased expression of iNOS and lower production of pro-inflammatory cytokines. Our data demonstrate the protective effects of celastrol in the chemoprevention of CAC, was and this effect correlated with a dampening of iNOS expression and with a decrease of inflammatory cytokine production. These results highlight the potential of celastrol as an effective agent for the chemoprevention of CAC in humans. Citation Format: Sung Hee Choi, Emily Baker, Byung-Gyu Kim, Gregory Tochtrop, John J. Letterio. Suppression of colitis-associated colon carcinogenesis by the natural triterpenoid celastrol. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-266. doi:10.1158/1538-7445.AM2015-LB-266