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Identification of novel antiangiogenic anticancer activities of deguelin targeting hypoxia‐inducible factor‐1 alpha
Author(s) -
Oh SeungHyun,
Woo Jong K.,
Jin Quanri,
Kang HyeJin,
Jeong JooWon,
Kim KyuWon,
Hong Waun Ki,
Lee HoYoung
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23075
Subject(s) - angiogenesis , mg132 , cancer research , vascular endothelial growth factor , biology , hif1a , hypoxia inducible factors , proteasome inhibitor , cell growth , pharmacology , chemistry , proteasome , microbiology and biotechnology , biochemistry , gene , vegf receptors
Hypoxia‐inducible factor 1 (HIF‐1) plays an essential role in tumor angiogenesis and growth by regulating the transcription of several genes in response to hypoxic stress and changes in growth factors. This study was designed to investigate the effects of deguelin on tumor growth and angiogenesis, and the mechanisms underlying the antitumor activities of deguelin. We show here that orally administered deguelin inhibits tumor growth and blocks tumor angiogenesis in mice. Deguelin decreased expression of HIF‐1α protein and its target genes, such as VEGF , in a subset of cancer cell lines, including H1299 lung cancer cells, and vascular endothelial cells in normoxic and hypoxic conditions. Overexpression of vascular endothelial growth factor by adenoviral vector infection abolished the antiangiogenic effects of deguelin on H1299 nonsmall cell lung cancer cells. Deguelin inhibited de novo synthesis of HIF‐1α protein and reduced the half‐life of the synthesized protein. MG132, a proteasome inhibitor, protected the hypoxia‐ or IGF‐induced HIF‐1α protein from deguelin‐mediated degradation. Our findings suggest that deguelin is a promising antiangiogenic therapeutic agent in cancer targeting HIF‐1α. Considering that HIF‐1α is overexpressed in a majority of human cancers, deguelin could offer a potent therapeutic agent for cancer. © 2007 Wiley‐Liss, Inc.