title: Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1alpha expression in human glioma cells by a proteasome-independent pathway: implications for in vivo therapy.
abstract: Angiogenesis is a critical step required for sustained tumor growth and tumor progression. The stimulation of endothelial cells by cytokines secreted by tumor cells such as vascular endothelial growth factor (VEGF) induces their proliferation and migration. This is a prominent feature of high-grade gliomas. The secretion of VEGF is greatly upregulated under conditions of hypoxia because of the transcription factor hypoxiainducible factor (HIF)-1alpha, which controls the expression of many genes, allowing rapid adaptation of cells to their hypoxic microenvironment. Flavopiridol, a novel cyclin-dependent kinase inhibitor, has been attributed with antiangiogenic properties in some cancer cell lines by its ability to inhibit VEGF production. Here, we show that flavopiridol treatment of human U87MG and T98G glioma cell lines decreases hypoxia-mediated HIF-1alpha expression, VEGF secretion, and tumor cell migration. These in vitro results correlate with reduced vascularity of intracranial syngeneic GL261 gliomas from animals treated with flavopiridol. In addition, we show that flavopiridol downregulates HIF-1alpha expression in the presence of a proteasome inhibitor, an agent that normally results in the accumulation and overexpression of HIF-1alpha. The potential to downregulate HIF-1alpha expression with flavopiridol treatment in combination with a proteasome inhibitor makes this an extremely attractive anticancer treatment strategy for tumors with high angiogenic activity, such as gliomas.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. newcoe01@med.nyu.edu
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Newcomb
authors.forename: M Aktar
authors.initials: MA
authors.lastname: Ali
authors.forename: Tona
authors.initials: T
authors.lastname: Schnee
authors.forename: Li
authors.initials: L
authors.lastname: Lan
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Lukyanov
authors.forename: Mary
authors.initials: M
authors.lastname: Fowkes
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Miller
authors.forename: David
authors.initials: D
authors.lastname: Zagzag
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy*; D006801:Humans; D000860:Hypoxia / Q000150:complications; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects
chemical_list: D001897:Boronic Acids; D005419:Flavonoids; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C423917:MG 262; D010880:Piperidines; D011480:Protease Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C077990:alvocidib; D020778:Matrix Metalloproteinase 2; D046988:Proteasome Endopeptidase Complex