Xian Wu1, Mingyue Song1, Minqi Wang1, Jinkai Zheng1,2, Zili Gao1, Fei Xu1, Guodong Zhang1, Hang Xiao1. 1. Department of Food Science, University of Massachusetts, Amherst, MA, USA. 2. Institute of Agro-Products Processing Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, P. R. China.
Abstract
SCOPE: Nobiletin (NBT) is a major citrus flavonoid with various health benefits. Herein, we investigated the colon cancer chemopreventive effects of NBT and its colonic metabolites in a colitis-associated colon carcinogenesis mouse model as well as in human colon cancer cell models. METHODS AND RESULTS: In azoxymethane/dextran sulfate sodium treated mice, oral administration of NBT effectively decreased both incidence and multiplicity of colonic tumors. NBT showed significant antiproliferative, proapoptotic, and anti-inflammatory effects in the mouse colon. HPLC analysis revealed that oral administration of NBT resulted in high levels of metabolites, i.e. 3'-demethylnobiletin (M1), 4'-demethylnobiletin (M2), and 3',4'-didemethylnobiletin (M3) in the colonic mucosa. In contrast, the colonic level of NBT was about 20-fold lower than the total colonic level of three metabolites. Cell culture studies demonstrated that the colonic metabolites of NBT significantly inhibited the growth of human colon cancer cells, caused cell-cycle arrest, induced apoptosis, and profoundly modulated signaling proteins related with cell proliferation and cell death. All of these effects were much stronger than those produced by NBT alone. CONCLUSION: Our results demonstrated that oral administration of NBT significantly inhibited colitis-associated colon carcinogenesis in mice, and this chemopreventive effect was strongly associated with its colonic metabolites.
SCOPE: Nobiletin (NBT) is a major citrus flavonoid with various health benefits. Herein, we investigated the colon cancer chemopreventive effects of NBT and its colonic metabolites in a colitis-associated colon carcinogenesismouse model as well as in humancolon cancer cell models. METHODS AND RESULTS: In azoxymethane/dextran sulfate sodium treated mice, oral administration of NBT effectively decreased both incidence and multiplicity of colonic tumors. NBT showed significant antiproliferative, proapoptotic, and anti-inflammatory effects in the mouse colon. HPLC analysis revealed that oral administration of NBT resulted in high levels of metabolites, i.e. 3'-demethylnobiletin (M1), 4'-demethylnobiletin (M2), and 3',4'-didemethylnobiletin (M3) in the colonic mucosa. In contrast, the colonic level of NBT was about 20-fold lower than the total colonic level of three metabolites. Cell culture studies demonstrated that the colonic metabolites of NBT significantly inhibited the growth of humancolon cancer cells, caused cell-cycle arrest, induced apoptosis, and profoundly modulated signaling proteins related with cell proliferation and cell death. All of these effects were much stronger than those produced by NBT alone. CONCLUSION: Our results demonstrated that oral administration of NBT significantly inhibited colitis-associated colon carcinogenesis in mice, and this chemopreventive effect was strongly associated with its colonic metabolites.
Authors: A Minagawa; Y Otani; T Kubota; N Wada; T Furukawa; K Kumai; K Kameyama; Y Okada; M Fujii; M Yano; T Sato; A Ito; M Kitajima Journal: Jpn J Cancer Res Date: 2001-12
Authors: Nadya M Morrow; Amy C Burke; Joshua P Samsoondar; Kyle E Seigel; Andrew Wang; Dawn E Telford; Brian G Sutherland; Conor O'Dwyer; Gregory R Steinberg; Morgan D Fullerton; Murray W Huff Journal: J Lipid Res Date: 2020-01-21 Impact factor: 5.922