Identification of novel antiangiogenic anticancer activities of deguelin targeting hypoxia-inducible factor-1 alpha.
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-1alpha 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-1alpha protein and reduced the half-life of the synthesized protein. MG132, a proteasome inhibitor, protected the hypoxia- or IGF-induced HIF-1alpha protein from deguelin-mediated degradation. Our findings suggest that deguelin is a promising antiangiogenic therapeutic agent in cancer targeting HIF-1alpha. Considering that HIF-1alpha is overexpressed in a majority of human cancers, deguelin could offer a potent therapeutic agent for cancer.
Oh
Seung-Hyun
SH
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Woo
Jong K
JK
Jin
Quanri
Q
Kang
Hye-Jin
HJ
Jeong
Joo-Won
JW
Kim
Kyu-Won
KW
Hong
Waun Ki
WK
Lee
Ho-Young
HY
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D017077:Culture Media, Conditioned; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
D020533:Angiogenesis Inhibitors; D017077:Culture Media, Conditioned; D015853:Cysteine Proteinase Inhibitors; D004338:Drug Combinations; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D007976:Leupeptins; D011509:Proteoglycans; D025801:Ubiquitin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D012402:Rotenone; C059485:matrigel; D003094:Collagen; D008156:Luciferases; D046988:Proteasome Endopeptidase Complex; C107676:deguelin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde