Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1α expression in human glioma cells by a proteasome-independent pathway:: Implications for in vivo therapy

被引:70
作者
Newcomb, EW
Ali, MA
Schnee, T
Lan, L
Lukyanov, Y
Fowkes, M
Miller, DC
Zagzag, D
机构
[1] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA
[2] NYU, Sch Med, Div Neuropathol, Dept Neurosurg, New York, NY 10016 USA
[3] NYU, Sch Med, Inst Canc, New York, NY 10016 USA
关键词
flavopiridol; proteasome inhibitor; hypoxia; HIF-1; alpha; VEGF; glioma;
D O I
10.1215/S1152851704000997
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 hypoxia-inducible factor (HIF)-1 alpha, 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-1 alpha 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-1 alpha expression in the presence of a proteasome inhibitor, an agent that normally results in the accumulation and overexpression of HIF-1 alpha. The potential to downregulate HIF-1 alpha 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.
引用
收藏
页码:225 / 235
页数:11
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