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Title: An investigation of the anticancer activity of plant bioactives and their associated microbial biotransformation products
Author: Allsopp, Philip
Awarding Body: University of Ulster
Current Institution: Ulster University
Date of Award: 2009
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Colon cancer is a complex and multifactorial disease and the colonic microbiota has been strongly implicated in its aetiology. The dynamic metabolic interaction between the colonic microbiota, dietary components and the colonic tissue are primary factors influencing the process of colon carcinogenesis. Human dietary habits strongly influence the development of sporadic colon cancer. However, characterising microbe-nutrient interactions and determining the effect of bacterial metabolic activity on colon cancer risk may help identify dietary components with potential cancer-preventing or promoting activities leading eventually to the construction of effective nutritional strategies. The practical and ethical problems associated with the use of cancer as an endpoint and the invasive nature of colonic sampling has made the use of in vitro culture models and biomarkers an attractive alternative for identifying nutrients that may reduce the risk of colon cancer. This, study set out to investigate the anticancer properties of plant bioactive compounds from hops (Humulus lupulus L) and bioactive components from plants of the agave genus (Agave tequilana & Agave angustifolia) on selected colon cancer biomarkers. The predominant prenylflavonoid present in beer, isoxanthohumol (Ix), which is weakly estrogenic, has been shown to undergo a degree of microbial transformation within the colon to 8-prenylnaringenin (8-PN) (the most potent phytoestrogen known), with inter-individual differences ranging from 0 to 80% conversion. Using a range of bioassays both Ix and 8-PN were shown to have similar anti-genotoxic (comet assay) and anti-invasive (matrigel assay) activity which would indicate that such activity is independent of estrogenicity. Ix was shown to alter Caco-2 cell proliferation and alter cell cycle kinetics at low concentrations compared to 8-PN. Ix also exhibited genotoxic activity at high concentrations (50~M) as well as significant cell cycle arrest (G2/M phase) raising concerns for safety as well as its potential application as a therapeutic anticancer compound. Future research would be directed at in vivo animal studies to determine if the activities observed in this study have any actual influence on tumourogenesis. The leaves of the plant Agave tequilana are a waste product of the tequila industry and medicinal practices by indigenous Mexican populations have led us to investigate the anticancer properties of the aqueous leaf extract. The observed anti-genotoxic activity of the aqueous agave leaf extract in this study would enable it to be considered as a potential cancer preventative supplement, although the observed systemic cytotoxic activity (lymphocytic Jurkat cells) highlights the need for caution and the necessity for further investigation into the extract's constituent active compounds and their systemic bioavailability. The simulated human intestinal microbial ecosystem (SHIME) culture model was used to investigate microbial and metabolic changes indicative of prebiotic activity of the fructan fraction from Agave angustifolia. Supplementation of the Agave fructan in the SHIME model stimulated lactobacilli and bifidobacterial populations and enhanced butyrate concentration. Furthermore, of particular interest was the reduced ammonium concentration in conjunction with elevated concentrations of short chain fatty acids in the descending colon vessel which suggests a reduction of proteolytic fermentation, a desirable change that has not previously- been noted in the descending colon with inulin type fructans. The promising results obtained in this study would need to be confirmed in vivo prior to evaluating the possible application of Agave fructan in human nutrition. The final study set out to investigate the effect of incubating SHIME effluent following treatment with Agave fructan or inulin type fructan (ITF) on several in vitro mammalian cell systems that model the development of cancer. Neither ITF, nor Agave fructan treated SHIME effluent were shown to have any influence on genotoxicity or to prevent H202 induced DNA damage when incubated with Caco-2 cells. However effluent from SHIME systems supplemented with either fructan type reduced Caco-2 monolayer permeability, particularly effluent from the ascending and descending colon vessels. Such an effect is indicative of improved barrier function and antitumour-promoting activity. Future research should be directed towards extending these in vitro studies to the in vivo situation to clarify the prebiotic effects of Agave fructan.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available