title: Nobiletin and its colonic metabolites suppress colitis-associated colon carcinogenesis by down-regulating iNOS, inducing antioxidative enzymes and arresting cell cycle progression.
abstract: Nobiletin (NOB) is a major citrus polymethoxyflavone (PMF) with various beneficial biological activities. We reported previously that dietary NOB significantly inhibited colitis-associated colon carcinogenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice, and the chemopreventive effects were associated with NOB metabolites found in the mouse colonic tissues. In this study, to better understand the role of colonic metabolites of NOB, we determined the anti-inflammation and anticancer effects of a mixture of NOB and its major metabolites (NOB-Met) at the concentrations equivalent to those found in colonic tissues of NOB-fed mice. The results demonstrated that NOB-Met effectively decreased the expression level of inducible nitric oxide synthase (iNOS), increased the level of heme oxygenase-1 (HO-1) and NADH quinone oxidoreductase 1 (NQO1) and up-regulated nuclear factor erythroid 2-related factor (Nrf2) signaling pathway in lipopolysaccharide (LPS)-stimulated macrophages. NOB-Met also caused a significant cell cycle arrest in human colon cancer cells. Validation study confirmed that dietary NOB led to the effects similar to those described above in the colon of AOM/DSS-treated mice. Specifically, dietary NOB significantly reduced the level of iNOS, up-regulated Nrf2-dependent enzymes and profoundly modulated key signaling proteins resulting in decreased cell cycle progression in the colonic tissue of AOM/DSS-treated mice. Overall, our findings demonstrated that dietary NOB led to the presence of NOB and its metabolites in the colonic tissue, which suppressed colitis-associated colon carcinogenesis via down-regulating iNOS, inducing antioxidative enzymes and arresting cell cycle progression.
authors.affiliation: Department of Food Science, University of Massachusetts Amherst, Amherst, MA, United States. Electronic address: xianwu@alumni.umass.edu.
authors.forename: Xian
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Food Science, University of Massachusetts Amherst, Amherst, MA, United States.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Food Science, University of Massachusetts Amherst, Amherst, MA, United States.
authors.forename: Zili
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Food Science, University of Massachusetts Amherst, Amherst, MA, United States; State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, Anhui, PR China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Food Science, University of Massachusetts Amherst, Amherst, MA, United States.
authors.forename: Minqi
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Food Science, University of Massachusetts Amherst, Amherst, MA, United States.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Food Science, University of Massachusetts Amherst, Amherst, MA, United States; Institute of Agro-Products Processing Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, PR China.
authors.forename: Jinkai
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Food Science, University of Massachusetts Amherst, Amherst, MA, United States. Electronic address: hangxiao@foodsci.umass.edu.
authors.forename: Hang
authors.initials: H
authors.lastname: Xiao
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D003092:Colitis / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology / Q000517:prevention & control*; D015536:Down-Regulation; D004798:Enzymes / Q000378:metabolism; D047309:Flavones / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008815:Mice, Inbred Strains; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D000975:Antioxidants; D004798:Enzymes; D047309:Flavones; D008070:Lipopolysaccharides; C008661:nobiletin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: Cell cycle; Chemoprevention; Colon carcinogenesis; Metabolites; Nobiletin; Nrf2; iNOS