German Title: Chemopräventives Potenzial von Se-angereichertem Brokoli und Grünkohlkeimlingen in vitro und bei menschlichem Prostatakrebs im Xenograft Modell
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Prostate cancer is the most commonly diagnosed malignancy in men in industrialized countries. Many epidemiologic studies support that dietary intake of chemopreventive agents may be protective against prostate cancer. From the several agents we focused on selenium and cruciferous vegetables. The first aim was to produce selenium enriched broccoli and to evaluate the effects. Spraying selenate onto broccoli leaves increased selenium contents in the broccoli without changing glucoraphanin contents. Se-enriched broccoli potently increases phase II detoxifying enzymes and Se-containing antioxidant enzymes in vitro, however 20% of dietary Se-enriched broccoli and the functional foods produced from it had no influence on enzyme induction and tumor growth in vivo in the LNCaP xenograft model although liver phase II enzymes were induced and sulforaphane metabolites were detectable in the mouse plasma. The second aim of this study was to investigate the effect of kale sprouts in the LNCaP xenograft model. Dietary kale sprouts for 6.5 weeks did not show growth inhibitory effects. However, we observed much evidence that kale sprouts reduced the development of prostate cancer and aggressiveness. First of all, the tumors contained less hemorrhage and necrotic areas. Also, invasion of mouse-derived cells into xenografts was reduced by the intervention. Although the vessel density was not different between the groups, vessel maturation in the kale sprout group was increased, which was indicated by increased pericyte coverage of endothelial cells. Vascular maturation was associated with down-regulation of the pro-angiogenic factors and up-regulation of an anti-angiogenic factor, angiostatin. According to the vascular maturation, hemorrhage could be prevented leading to prevention of necrosis. As the third part of the study, we further investigated effects of kale sprouts on epigenetic histone modifications. Dietary kale sprouts increased histone acetylation associated with increased HAT levels rather than inhibition of HDAC activity in the LNCaP xenograft model. The change of balance between HAT and HDAC by was associated with increased histone acetylation at the promoter of p21 and its gene expression. Dietary kale sprouts indeed increased mitotic arrest which is associated with p21 gene induction. Interestingly, these effects were not only limited to the xenograft model but could also be shown in human PBMC after intervention. In summary, the presented thesis describes novel mechanistic modes of cruciferous vegetables, which contain potent cancer chemopreventive compounds. Importantly these effects were shown in relevant concentration that they could be used as a dietary supplement.
Translation of abstract (German)
Zusammenfassend beschreibt die vorliegende Arbeit neue mechanistische Aktivitäten von Cruciferen, die sehr potente prostatachemopräventive Agenzien beinhalten. Selendüngung trägt dazu bei die Prostatakrebs-präventiven Effekte von Brokkoli zu erhöhen, indem die Selenhaltigen antioxidativen Enzyme induziert werden, allerdings ohne einen Einfluss auf das Tumorwachstum zu haben. Zum ersten Mal wurde gezeigt, dass Grünkohlkeimlinge chemopräventives Potenzial besitzen, da diese die Ausbildung von Blutgefäßen erhöhen und Blutungen sowie Nekrosen im Tumor verringern. Ein weiterer wichtiger Angriffspunkt von Grünkohlkeimlingen ist die Histonacetylierung. Erwähnenswert hierbei sind die geringen Konzentrationen der eingesetzten chemopräventiven Agenzien, die jenen Konzentrationen entsprechen, die mit Nahrungsergänzungsmitteln mit der täglichen Nahrung aufgenommen werden.
|Supervisor:||Rausch, Prof. Dr. Thomas|
|Date of thesis defense:||17. December 2010|
|Date Deposited:||20. Dec 2010 12:18|
|Faculties / Institutes:||Service facilities > Centre for Organismal Studies Heidelberg (COS)
Service facilities > German Cancer Research Center (DKFZ)
|Subjects:||570 Life sciences|
|Controlled Keywords:||Prostatakrebs, Prävention, Kreuzblütler, Selen|
|Uncontrolled Keywords:||prostate cancer , Chemoprevention , Cruciferous vegetables , Selenium|