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Document Type

Campus-Only Access for Five (5) Years

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Food Science

Year Degree Awarded

2016

Month Degree Awarded

February

First Advisor

Hang Xiao

Second Advisor

Eric A. Decker

Third Advisor

Guodong Zhang

Fourth Advisor

Richard J. Wood

Subject Categories

Food Chemistry | Food Science | Molecular, Genetic, and Biochemical Nutrition

Abstract

Colon cancer is one of the major global public health issues, which severely threatens human health. Polymethoxyflavones (PMFs), a unique class of flavonoids, are abundantly and almost exclusively found in the peel of sweet oranges (Citrus sinensis) and mandarin oranges (Citrus reticulata). Nobiletin (NBT) is a major citrus flavonoid that has shown various health benefits, including anti-inflammation and anti-carcinogenesis. To better understand the chemopreventive effects of NBT, we systematically investigated the inhibitory effects of dietary NBT on colitis-associated colon carcinogenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice. We found that oral administration of NBT effectively decreased both incidence and multiplicity of colonic tumors. NBT showed significant anti-proliferative, pro-apoptotic and anti-inflammatory effects in the mouse colon. HPLC analysis revealed that oral administration of NBT resulted in high levels of metabolites 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.

4'-Demethylnobiletin (4DN) is a major metabolite of NBT, and its tissue level was found to be much higher than that of NBT after oral administration of NBT in mice. Our results showed that 4DN effectively inhibited lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 cells macrophage cells, such as production of NO, PGE2, and gene expression of iNOS and COX-2 via modulating NF-κB, AP-1 and Nrf2 pathways. Moreover, 4DN suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated skin inflammation in mice, and its effect was much stronger than that produced by NBT. The anti-inflammatory effects by 4DN were associated with suppression of TPA-stimulated production of IL-1β, IL-6 and TNF-α, and reduction of protein expression of iNOS, COX-2 and MMP-9. Furthermore, the results indicated that 4DN was able to up-regulate the expression levels of phase II anti-oxidative enzymes HO-1 and NQO1 in TPA-treated mouse ears.

Accumulating studies suggests that cancer chemopreventive agents in combination may act synergistically and produce enhanced protective effects against carcinogenesis than each individual agent. Next we investigated the synergistic anticancer effects of NBT and atorvastatin (ATST, a lipid-lowering drug) in combination in human colon cancer cells and an AOM-induced colon carcinogenesis rat model. Co- treatments of NBT/ATST at half doses produced much stronger inhibitory effects on colon cancer cells compared to those produced by NBT or ATST alone at full doses. Isobologram analysis confirmed these two compounds have strong synergistic interaction. Animal study showed that oral intake of NBT/ATST in combination produced synergistic inhibitory effect on tumor incidence and multiplicity in comparison to those produced by individual NBT or ATST. Our results also indicated that co-treatment of NBT/ATST had much stronger anti-proliferative, pro-apoptotic and anti-inflammatory effects in AOM-treated rats than that produced by NBT or ATST alone.

In conclusion, these studies provided a scientific basis for using NBT as a nutraceutical for colon cancer chemoprevention, as well as using NBT and ATST in combination for enhanced cancer protective efficacy.

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