Flavonoids in Pancreatic Carcinogenesis & Angiogenesis
Principle Investigator: Joe O. Hines, MD
Co-Principle Investigator: Paul W. N. Lee, PhD
Research Assistant: Eliane Angst, MD
Collaborator: David Dawson, MD
Hypothesis: We hypothesize that flavonoids prevent the progression to pancreatic cancer, and that flavonoids may act as a chemotherapeutic in established pancreatic cancer.
Specific Aim I: Determine the ability of flavonoids to prevent the progression of pancreatic intraepithelial neoplasia (PanIN) to invasive pancreatic ductal adenocarcinoma using a novel transgenic pancreatic cancer animal model.
Specific Aim 2: Assess the effect of flavonoids on immortalized human pancreatic cancer cell lines in an orthotopic xenograph model.
Genistein
• tyrosine kinase inhibitor
• induces differentiation
• inhibits topoisomerase II
• inhibit angiogenesis
• combined with the TRAIL/Apo2L decreases pancreatic cancer cell proliferation
in vitro and tumor volume in vivo
• STAT3 is modulated by genistein in Panc-1 and MIA PaCA-2 and is inhibited at 10 _M
• increases growth inhibition and apoptosis induced by cisplatin, docetaxel, and
doxorubicin in PaCa cells
• in vivo, genistein shown to increase growth inhibition w/ gemcitabine or cisplatin
• genistein decreases CXCL8 and CXCL1
Apigenin
• flavonoid isomer of genistein, with hydroxylations at positions 5, 7, and 4’
• inhibits VEGF secretion with potency comparable to that of genistein
• inhibits hypoxia-inducible factor 1 (HIF-1) alpha
• inhibits TNF-alpha-induced IL-6 and CXCL8 production
Quercetin
• decreased primary tumor growth, increased apoptosis and prevented metastasis in
nude mice implanted with human pancreatic cells
• mitochondrial depolarization, cytochrome-c release followed by caspase-3 activation
• nuclear factor-kappa B activity is inhibited
• inhibit TNF-alpha-induced IL-6 and CXCL8 production (NFkB?)
Specific Aim 1, Preventive Model
Human Pancreatic Cancer Cells
Specific Aim 2, Treatment Model: orthotopic xenograph in nude mice