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Title: Chemopreventive potential of dietary polyphenols
Author: Magnay, Fiona-Ann
ISNI:       0000 0001 3616 3969
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 2005
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The chemopreventive potential of a wide variety of structurally diverse polyphenols were initially evaluated for their apoptotic-inducing activity, using HCT-8 ileocecal adenocarcinoma cells. Apoptosis was measured by fluorescence microscopy and morphological criteria. (-)-Epigallocatechin-3-gallate (EGCG), theaflavins, curcumin and the grape seed polymer were found to be the most potent inducers of apoptosis, at concentrations physiologically relevant to humans. In contrast to the observation in HCT-8 cancerous cells, polyphenol-induced apoptosis was substantially lower in ICE-6 non-cancerous epithelial cells. The aforementioned "active" apoptotic polyphenols were subsequently assessed for their ability to activate direct and indirect caspases. Activation of downstream caspase- 3 and -7, and upstream caspase-9, in HCT-8 cells, implies that an intrinsic (intracellular) caspase cascade is involved in polyphenol-induced apoptosis. Potential pro-oxidant and/or antioxidant mechanisms and interactions, through which polyphenols may initiate apoptosis in HCT-8 cells, were investigated by assessing the impact of various agents, including antioxidant enzymes and hydrogen peroxide (H2O2), upon apoptotic induction. Catalase and superoxide dismutase substantially reduced EGCG-induced apoptosis. In contrast, a substantial rise in EGCG-induced apoptosis was observed in the presence of both H2O2 and Fe3+. Moreover, H2O2 production was apparent in the presence of EGCG. These data thus suggest that polyphenols induce apoptosis via a pro-oxidant mechanism, which appears to involve the generation of H2O2 and transition metals in a Fenton type reaction. A range of naturally-occurring and synthetic polyphenolic compounds was assessed for their ability to bind to the Ah receptor, as agonists and/or antagonists, in HlLl.lc2 cells, using the chemically activated luciferase gene expression (CALUX) assay. Although the flavonoid 3',4'-dimethoxyflavone appears to competitively antagonise 2,3,7,8-tetrachlorodibenzo-p-dioxin binding at the Ah receptor, the other flavonoids tested failed to indicate reliable or reproducible interactions with the Ah receptor.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available