The Cellular and Molecular Properties of Flavinoids in Prostate Cancer Chemoprevention
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. These findings lay the foundation for further studies of flavonoids in clinical chemoprevention trials.
Flavonoids, Prostate Cancer, Cell cycle, Apoptosis, Senescence, TRAMP, Microarray, Diet
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