Potent suppression of both spontaneous and carcinogen-induced colitis-associated colorectal cancer in mice by dietary celastrol supplementation
| Autor: | Byung-Gyu Kim, John J. Letterio, Emily C. Barker, Gregory P. Tochtrop, Sung Hee Choi, Ji Hee Yoon |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Cancer Research Carcinogenesis Anti-Inflammatory Agents Inflammation Pharmacology Proinflammatory cytokine Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Animals Medicine Colitis biology business.industry Azoxymethane Interleukin General Medicine biology.organism_classification medicine.disease Triterpenes Mice Inbred C57BL 030104 developmental biology chemistry Celastrol 030220 oncology & carcinogenesis Dietary Supplements Carcinogens biology.protein Cyclooxygenase Tripterygium wilfordii medicine.symptom Colorectal Neoplasms Pentacyclic Triterpenes business Inflammation Microenvironment and Prevention |
| Zdroj: | Carcinogenesis. 39:36-46 |
| ISSN: | 1460-2180 0143-3334 |
| DOI: | 10.1093/carcin/bgx115 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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