Potent suppression of both spontaneous and carcinogen-induced colitis-associated colorectal cancer in mice by dietary celastrol supplementation

These findings indicate the long term tolerability and chemopreventive potential of dietary celastrol in colitis-associated colorectal cancer, a disease for which current preventive therapies are accompanied by severe and unwanted side effects. Abstract Celastrol is an anti-inflammatory natural trit...

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Published in:Carcinogenesis (New York) 2018-01, Vol.39 (1), p.36-46
Main Authors: Barker, Emily C, Kim, Byung-Gyu, Yoon, Ji Hee, Tochtrop, Gregory P, Letterio, John J, Choi, Sung Hee
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents - pharmacology
Carcinogenesis - drug effects
Carcinogens - toxicity
Colitis - complications
Colorectal Neoplasms - etiology
Colorectal Neoplasms - pathology
Dietary Supplements
Inflammation, Microenvironment and Prevention
Male
Mice
Mice, Inbred C57BL
Pentacyclic Triterpenes
Triterpenes - pharmacology
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Summary:These findings indicate the long term tolerability and chemopreventive potential of dietary celastrol in colitis-associated colorectal cancer, a disease for which current preventive therapies are accompanied by severe and unwanted side effects. Abstract Celastrol is an anti-inflammatory natural triterpenoid, isolated from the herb Tripterygium wilfordii or thunder god vine. Here, we define mechanisms mediating anti-inflammatory activity of celastrol and demonstrate efficacy of a dietary celastrol supplement for chemoprevention of inflammation-driven carcinogenesis in mice. Dietary celastrol (31.25 ppm in rodent diet from 8 weeks to 25 weeks of age) is well tolerated and protects against LPS-induced acute inflammation in C57BL/6 mice, potently suppressing LPS-induction of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, Interleukin (IL)-6 and IL-1β. To test whether dietary celastrol suppresses inflammation-driven colorectal cancer (CRC), we employed a unique model of spontaneous, inflammation-driven CRC in mice harboring a germ line deletion of the p27Kip1 gene and a T cell-specific deletion of Smad4 gene (Smad4co/co;Lck-crep27Kip1-/-or DKO), which develop severe intestinal inflammation and carcinogenesis as early as 3 months of age. Exposure of DKO mice to daily dietary celastrol (12.5 ppm in diet) from 6 weeks of age significantly suppressed development of colitis-associated CRC (CAC). Celastrol chemoprevention of CAC in this new model of intestinal neoplasia was associated with significant suppression of iNOS at 4 months of age, and iNOS, COX-2 and NFκB at 6 months of age, with significant reduction in inflammatory cytokines, IL-6 and IL-1β. Chemoprevetion of CAC by dietary celastrol was further confirmed in the model of azoxymethane (AOM) plus dextran sodium sulfate (DSS)-induced carcinogenesis in C57BL/6 mice. These data suggest the potential for celastrol as a safe and effective dietary supplement in the chemoprevention of CAC in humans.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgx115