The Cellular and Molecular Properties of Flavinoids in Prostate Cancer Chemoprevention
type: CreativeWork
description: Flavonoids are a large class of dietary polyphenols that have emerged as candidate agents for chemoprevention in prostate cancer. Despite the large number of known flavonoids (over 9000), only a few have been studied in prostate cancer to date. The work presented in this thesis describes the identification of novel anti-proliferative flavonoids, their molecular effects on cell cycle and related proliferation and survival pathways, and their chemopreventive properties in a murine model of prostate carcinogenesis. We identified several novel flavonoids with potent anti-proliferative effects in human prostate cancer cells in vitro. Non-prostate cell lines were generally resistant to the effect of these flavonoids. Two of the most potent flavonoids identified, 2,2-dihydroxychalcone (DHC) and fisetin, induced S and G2 phase cell cycle arrest in LNCaP and PC3 prostate cancer cells. Gene expression studies employing oligonucleotide microarray demonstrated profound down-regulation in gene expression of 75 key cell cycle (predominantly G2 and M phase) genes by DHC and fisetin, and the enhanced expression of 50 stress-response genes with important roles in cell proliferation and survival. DHC and fisetin induced apoptosis, but not accelerated senescence, in prostate cancer cells. The chemopreventive effect of 4 flavonoids identified from the in vitro studies was examined in an autochthonous murine model of prostate cancer (TRAMP). Mice were administered diets supplemented with 1% DHC, 1% fisetin or a combination of flavonoids (0.25% DHC, 0.25% fisetin, 0.25% quercetin, 0.25% luteolin) for 32 weeks. We demonstrated a significant reduction in genitourinary weight, and a reduction in prostate cancer grade in mice administered 1% DHC and combination diets. Flavonoid supplementation was, however, associated with gastrointestinal toxicity in some mice. Liquid chromatography-mass spectrometry demonstrated the accumulation of high levels of flavonoid in the prostates of TRAMP mice. T…
abstract: Flavonoids are a large class of dietary polyphenols that have emerged as candidate agents for chemoprevention in prostate cancer. Despite the large number of known flavonoids (over 9000), only a few have been studied in prostate cancer to date. The work presented in this thesis describes the identification of novel anti-proliferative flavonoids, their molecular effects on cell cycle and related proliferation and survival pathways, and their chemopreventive properties in a murine model of prostate carcinogenesis. We identified several novel flavonoids with potent anti-proliferative effects in human prostate cancer cells in vitro. Non-prostate cell lines were generally resistant to the effect of these flavonoids. Two of the most potent flavonoids identified, 2,2-dihydroxychalcone (DHC) and fisetin, induced S and G2 phase cell cycle arrest in LNCaP and PC3 prostate cancer cells. Gene expression studies employing oligonucleotide microarray demonstrated profound down-regulation in gene expression of 75 key cell cycle (predominantly G2 and M phase) genes by DHC and fisetin, and the enhanced expression of 50 stress-response genes with important roles in cell proliferation and survival. DHC and fisetin induced apoptosis, but not accelerated senescence, in prostate cancer cells. The chemopreventive effect of 4 flavonoids identified from the in vitro studies was examined in an autochthonous murine model of prostate cancer (TRAMP). Mice were administered diets supplemented with 1% DHC, 1% fisetin or a combination of flavonoids (0.25% DHC, 0.25% fisetin, 0.25% quercetin, 0.25% luteolin) for 32 weeks. We demonstrated a significant reduction in genitourinary weight, and a reduction in prostate cancer grade in mice administered 1% DHC and combination diets. Flavonoid supplementation was, however, associated with gastrointestinal toxicity in some mice. Liquid chromatography-mass spectrometry demonstrated the accumulation of high levels of flavonoid in the prostates of TRAMP mice. T…
author: Haddad, Ahmed Qais
language: en_ca
keywords: Flavonoids, Prostate Cancer, Cell cycle, Apoptosis, Senescence, TRAMP, Microarray, Diet
date published: 2008-07-31T21:34:49Z
date modified: 2026-07-27T21:28:22Z
provider: University of Toronto
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Toronto

PropertyValue
property ID: Handle
value: http://hdl.handle.net/1807/11209