3',4',5',5,7-Pentamethoxyflavone (PMF) is a naturally occurring flavone found in the leaves of Murraya paniculata and the fruits of Neoraputia magnifica. PMF has been shown to possess potential promise as a colorectal cancer (CRC) chemopreventive agent as it significantly inhibited adenoma development in the ApCMinl+ mouse, a model of gastrointestinal cancer. The chemopreventive activity of PMF was superior to that of two closely related flavone analogues apigenin and tricin. The aim of the work described in this thesis was to elucidate the mechanisms by which PMF can interfere with carcinogenesis. PMF was compared to tricin and apigenin in its abilities to inhibit growth, arrest cell cycle and elicit apoptosis in APC 1 0.1 cells, derived from ApCMinl+ mice. Cells were incubated with these agents (10 IlM, 24 h) and cDNA microarray analysis was performed to delineate changes in gene expression caused by these flavones. Gene changes were validated using reverse transcriptase-PCR and Western blot. PMF was administered to ApCMinl+ mice to assess its effects on protein expression in adenomas. PMF was the most growth-inhibitory of the three flavones with an ICso of 5 IlM. It arrested the cell cycle at G, and G2 phases and induced a two-fold increase in apoptosis. In the microarray study PMF modulated several key signalling pathways, most notably those involving Wnt, PI3KJAktlGSK3p and JAKJSTAT. In cells in vitro PMF significantly altered expression of Wnt8b, Wnt3a, TCF4, p-catenin, GSK3p, survivin, pSTAT3 and MCM7. In mice in vivo PMF, at a dietary dose which significantly reduced adenoma development, altered only p-catenin and MCM7 protein levels. These differences were only observed in the adenomas and not the normal mucosa. GSK3 p, p- Catenin and MCM7 may play a role in the CRC chemopreventive activity of PMF.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:551829 |
| Date | January 2012 |
| Creators | Fong, Isabel Lim |
| Contributors | Gescher, Andreas |
| Publisher | University of Leicester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2381/10376 |
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