Off-campus UMass Amherst users: To download campus access dissertations, please use the following link to log into our proxy server with your UMass Amherst user name and password.

Non-UMass Amherst users: Please talk to your librarian about requesting this dissertation through interlibrary loan.

Dissertations that have an embargo placed on them will not be available to anyone until the embargo expires.

Document Type

Campus-Only Access for Five (5) Years

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Food Science

Year Degree Awarded

2017

Month Degree Awarded

February

First Advisor

Hang Xiao

Subject Categories

Food Biotechnology | Food Chemistry

Abstract

Cancer has been a leading cause of morbidity and mortality worldwide and characterized by the uncontrolled cell proliferation and an absence of cell death. Polymethoxyflavones (PMFs) is a unique class of flavonoids that almost exclusively found in the peel of citrus fruit. Studies have shown that PMFs exhibited numerous health promoting effects, including anti-carcinogenic and anti-inflammatory ones. Nobiletin (5,6,7,8,3’,4’-hexamethyoxflavone, NBT) is a major citrus flavonoid and has been the most studied PMFs for its potential health benefits. 5-Demethylnobiletin (5-hydroxy-6,7,8,3’,4’-pentamethoxyflavone, 5DN) is a unique flavonoid found in citrus fruits with potential chemopreventive effects against human cancers.

In this dissertation, we first determined the inhibitory effects of 5DN and its two major metabolites in the in the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis mouse model as well as in human and mouse lung cancer cell models. In NNK-treated female A/J mice, dietary administration of 5DN significantly decreased both lung tumor multiplicity and tumor volume. Immunohistochemical analysis showed strong anti-proliferative effects of 5DN in lung tumors. Two major metabolites of 5DN, named 5,3ʹ-didemethylnobiletin (M1) and 5,4ʹ-didemethylnobiletin (M2), were found in the lung tissue of 5DN-fed mice. Cell culture studies demonstrated that 5DN, M1 and M2 significantly inhibited the growth of human and mouse lung cancer cells by causing cell cycle arrest, inducing apoptosis and modulating key signaling proteins related to cell proliferation and cell death. Interestingly, the metabolites of 5DN, especially M1 produced much stronger inhibitory effects on both human and mouse lung cancer cells than those produced by 5DN itself.

Combination of different bioactive agents may produce enhanced bioactive effects due to their synergistic interactions. Our previous study had demonstrated that the combination of NBT and atorvastatin (ATST, a cholesterol-lowering drug) exerted strong synergistic inhibition on lung cancer cells growth. Herein we investigated the in vivo efficacy and possible synergistic inhibitory effect of NBT/ATST combination in NNK-induced lung tumorigenesis mouse model. We found that NBT/ATST half dose combination synergistically produced much stronger inhibition on lung tumor multiplicity and tumor burden than those produced by individual treatment with NBT or ATST at full dose. The inhibition was associated with suppressed cell proliferation and enhanced apoptosis in adenoma as determined by immunohistochemistry.

Chronic inflammation is implicated as a risk factor for many diseases including colorectal cancer. Growing evidence has demonstrated that certain dietary agents can inhibit inflammation and to prevent the progression of cancer. 5DN has been reported to have anti-inflammatory and anti-carcinogenic activities in cell culture studies previously. Therefore, we demonstrated that dietary 5DN significantly inhibit tumor incidence, multiplicity and tumor burden in AOM/DSS-induced colon carcinogenesis mice model. The inhibitory effect of 5DN was closely by it colonic metabolites, namely M1, M2, and M3. Cell culture study indicated that the metabolites, especially M1, had more potent activity in inhibiting the growth of HCT116 human colon cancer cell when compared to 5DN. And the inhibition was associated with the induction of cell cycle arrest and apoptosis , as well as the modulation the expression of key signaling proteins that related to cell proliferation and apoptosis.

Share

COinS