Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Due to its pattern of increased incidence and mortality rates in Western countries, lifestyle factors, particularly diet, have been implicated in the aetiology of this disease. Recently, interest in the consumption of polyphenols, especially abundant in berries, has received a great deal of attention due to the putative anticancer activity of these compounds. In vivo, polyphenols undergo digestive conditions post consumption that alters the structure and possibly the function of these compounds. The focus of this study was firstly to produce berry extracts which had undergone in vitro simulated gastric and pancreatic digestion followed by fermentation of this colon-available extract with human faecal innocula. Secondly, in order to evaluate the putative anticancer activity of these extracts in vitro, their effect on models of colorectal cancer representing the key stages of initiation, promotion and invasion were investigated. Whole berry extracts and isolated berry components have previously been shown to modulate cellular functions involved in carcinogenesis such as cell cycle and proliferation in in vitro models of key stages of colon cancer. In the present study the bioactivity of digested and fermented extracts was demonstrated at a physiologically relevant dose range. Colon-available and fermented berry extracts significantly reduced hydrogen peroxide-induced DNA damage and relative mutation frequency in HT29 and HT29 (G 17 neo) cells respectively at non-toxic concentrations (0 - 50 ug/ml GAE). The extracts also inhibited invasion of HTl15 cells independent from migration. There was limited difference in the magnitude of effect between berry types; the exception was that only colon-available lingonberry extract was able to modulate proliferation and cell cycle progression ofHT29 cells at 50 ug/ml GAE. Also only a slight decrease in bioactivity was observed after in vitro fermentation. Due to the effectiveness of colon-available lingonberry extract in modulating several models of stages of colon cancer in HT29 cells, its effect on gene and protein expression was evaluated. These results were suggestive that this extract modulated the biological activity of cells in in vitro models of colorectal cancer through inducing transcription of genes responsible to halt the cell cycle and those involved in DNA damage repair. Preliminary work of an exploratory nature revealed that colon-available lingonberry extract caused changes in the metabolome of HT29 cells and may be of importance in modulating bioactivity of the cell although the individual metabolites were not identified. Overall this work has illustrated that colon-available and fermented berry extracts retain their biological activity in in vitro models of colorectal cancer, despite modification to their structures. The fact that breakdown products and metabolites can modulate cellular functions associated with colon cancer, similar to the parent compounds, may aid in the understanding of the mechanisms involved in modulating the pathophysiology of colorectal cancer.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:551561 |
| Date | January 2010 |
| Creators | Brown, Emma Marie |
| Publisher | University of Ulster |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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