Abstract 2258: Celastrol shows chemopreventive properties in an inflammatory driven model for colon cancer via induction of Nrf2 transcription.

Abstract

Abstract Celastrol is a natural triterpenoid isolated from the medicinal herb Triptyrgium wilfordii or Thunder of God vine. Celastrol has been shown to have a broad range of anti-inflammatory and anti-cancer activities. A mouse model for inflammatory-driven colon carcinogenesis combines a conditional T-cell deletion of the Smad4 gene with germ line deletion of the p27Kip1 gene. These genetic deletions result in spontaneous inflammation of the intestinal tract and associated early and aggressive development of cancer in the epithelia of both the small intestine and colon. In this study, administration of celastrol as a dietary supplement at a dose of 2 mg/kg is shown to be an effective strategy for cancer chemoprevention in this mouse model of colon carcinogenesis. Mice of this strain on a celastrol-supplemented diet had increased overall health and increased survival compared to mice receiving control diet. In vivo, celastrol was observed to increase the otherwise suppressed expression of cytoprotective Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) target genes (in comparison to wild type) and also to decrease expression of inducible nitric oxide synthase and accumulation of circulating nitric oxide in serum. In vitro, celastrol also induces antioxidant and cytoprotective activity through the induction of Nrf2 transcription as confirmed using macrophages derived from bone marrow of Nrf2-/- mice compared to wildtype. Celastrol induces the expression of many known Nrf2 target genes, including Hemeoxygenase-1, NAD(P)H quinone reductase-1, glutathione-S reductase, catalase and Nrf2 itself. This activity is abrogated in macrophages from Nrf2-/- mice. These data provide additional mechanistic insight on the potent anti-inflammatory activity of celastrol and present a rationale to further explore the capacity of dietary celastrol to suppress carcinogenesis in other, classical models of colon carcinogenesis with an emphasis on future potential for clinical translation. Citation Format: Emily Barker, John J. Letterio, Gregory P. Tochtrop. Celastrol shows chemopreventive properties in an inflammatory driven model for colon cancer via induction of Nrf2 transcription. [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 2258. doi:10.1158/1538-7445.AM2013-2258