PMID- 14692041
OWN - NLM
STAT- MEDLINE
DCOM- 20040120
LR  - 20161124
IS  - 0008-543X (Print)
IS  - 0008-543X (Linking)
VI  - 100
IP  - 1
DP  - 2004 Jan 1
TI  - Antiangiogenic activity of genistein in pancreatic carcinoma cells is mediated by 
      the inhibition of hypoxia-inducible factor-1 and the down-regulation of VEGF gene 
      expression.
PG  - 201-10
AB  - BACKGROUND: Previous reports indicate that Genistein, a naturally occurring 
      isoflavonoid, exhibits strong antiangiogenic activity. The underlying mechanism 
      of inhibition, however, remains unclear. Among the biologic effects of Genistein 
      are the inhibition of tyrosine kinases and the inhibition of hypoxic activation 
      of hypoxia-inducible factor-1 (HIF-1), one of the main regulators of VEGF gene 
      expression. METHODS: Hypoxic cell culture was performed in a modular incubator 
      chamber. Vascular endothelial growth factor (VEGF) protein secretion was measured 
      using the enzyme-linked immunosorbent assay, binding of DNA by HIF-1 was measured 
      using the electrophoretic mobility shift assay, and mRNA quantification was 
      performed using Northern blot analysis. Pancreatic carcinoma was studied in an 
      orthotopic murine model. Angiogenesis in vivo was quantified by staining 
      xenograft tumors for endothelial cell markers. RESULTS: VEGF protein secretion 
      was dose-dependently suppressed with increasing doses of Genistein. Furthermore, 
      treatment of pancreatic carcinoma cells with Genistein led to impaired activation 
      of HIF-1 under hypoxic culture conditions. Northern blot analysis indicated that 
      VEGF mRNA expression decreased upon treatment with Genistein, both under normoxic 
      and hypoxic culture conditions. In vivo, Genistein inhibited tumor growth for 
      xenograft pancreatic carcinoma cells, whereas extensive hypoxia was observed in 
      xenograft tumors and was not influenced by Genistein therapy. Similarly, 
      decreased VEGF mRNA levels were observed in Genistein-treated Capan-1 xenograft 
      tumors. CONCLUSIONS: The current study indicates that the previously reported 
      antiangiogenic activity of Genistein probably is mediated by the inhibition of 
      HIF-1, an important regulator of VEGF gene homeostasis, particularly under 
      low-oxygen conditions. Therefore, this bioactive compound may well be beneficial 
      to patients with pancreatic carcinoma.
CI  - Copyright 2003 American Cancer Society.
FAU - Buchler, Peter
AU  - Buchler P
AD  - Department of Surgery, School of Medicine, University of California at Los 
      Angeles, Los Angeles, California, USA. peter.buechler@med.uni-heidelberg.de
FAU - Reber, Howard A
AU  - Reber HA
FAU - Buchler, Markus W
AU  - Buchler MW
FAU - Friess, Helmut
AU  - Friess H
FAU - Lavey, Robert S
AU  - Lavey RS
FAU - Hines, Oscar J
AU  - Hines OJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
RN  - 0 (Antineoplastic Agents)
RN  - 0 (DNA, Complementary)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - DH2M523P0H (Genistein)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Blotting, Northern
MH  - Carcinoma/*pathology
MH  - DNA, Complementary
MH  - DNA-Binding Proteins/*biosynthesis/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation
MH  - Electrophoretic Mobility Shift Assay
MH  - *Gene Expression Regulation, Neoplastic
MH  - Genistein/*pharmacology
MH  - Helix-Loop-Helix Motifs
MH  - Homeostasis
MH  - Humans
MH  - Hypoxia
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Immunohistochemistry
MH  - Mice
MH  - Mice, Nude
MH  - *Neovascularization, Pathologic
MH  - Nuclear Proteins/*biosynthesis/pharmacology
MH  - Pancreatic Neoplasms/*pathology
MH  - RNA, Messenger/analysis
MH  - Transcription Factors
MH  - Transplantation, Heterologous
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A/*biosynthesis/pharmacology
EDAT- 2003/12/24 05:00
MHDA- 2004/01/21 05:00
CRDT- 2003/12/24 05:00
PHST- 2003/12/24 05:00 [pubmed]
PHST- 2004/01/21 05:00 [medline]
PHST- 2003/12/24 05:00 [entrez]
AID - 10.1002/cncr.11873 [doi]
PST - ppublish
SO  - Cancer. 2004 Jan 1;100(1):201-10. doi: 10.1002/cncr.11873.