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Neuro-Oncology 2005 7(3):225-235; doi:10.1215/S1152851704000997
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© 2005 by the Society forNeuro-Oncology

Flavopiridol downregulates hypoxia-mediated hypoxia-induciblefactor-1{alpha} expression in human glioma cells by a proteasome-independentpathway: Implications for in vivo therapy

Elizabeth W. Newcomb2, M. Aktar Ali, Tona Schnee, Li Lan, Yevgeniy Lukyanov, Mary Fowkes, Douglas C. Miller and David Zagzag

Department of Pathology (E.W.N., M.A.A., T.S., L.L.,Y.L., M.F., D.C.M., D.Z.); Division of Neuropathologyand Department of Neurosurgery (D.C.M., D.Z.); NewYork University Cancer Institute (E.W.N., D.C.M., D.Z.), New York UniversitySchool of Medicine, New York, NY 10016, USA

2 Address correspondence to Elizabeth W. Newcomb, Department of Pathology, NewYork University School of Medicine, 550 First Avenue, MSB531, New York, NY10016(newcoe01{at}med.nyu.edu).


  Abstract

Angiogenesis is a critical step required for sustained tumor growth andtumor progression. The stimulation of endothelial cells by cytokines secretedby tumor cells such as vascular endothelial growth factor (VEGF) induces theirproliferation and migration. This is a prominent feature of high-gradegliomas. The secretion of VEGF is greatly upregulated under conditions ofhypoxia because of the transcription factor hypoxiainducible factor(HIF)-1{alpha}, which controls the expression of many genes, allowing rapidadaptation of cells to their hypoxic microenvironment. Flavopiridol, a novelcyclin-dependent kinase inhibitor, has been attributed with antiangiogenicproperties in some cancer cell lines by its ability to inhibit VEGFproduction. Here, we show that flavopiridol treatment of human U87MG and T98Gglioma cell lines decreases hypoxia-mediated HIF-1{alpha} expression, VEGFsecretion, and tumor cell migration. These in vitro results correlate withreduced vascularity of intracranial syngeneic GL261 gliomas from animalstreated with flavopiridol. In addition, we show that flavopiridoldownregulates HIF-1{alpha} expression in the presence of a proteasomeinhibitor, an agent that normally results in the accumulation andoverexpression of HIF-1{alpha}. The potential to downregulate HIF-1{alpha}expression with flavopiridol treatment in combination with a proteasomeinhibitor makes this an extremely attractive anticancer treatment strategy fortumors with high angiogenic activity, such as gliomas.

Received November 5, 2004; Accepted February 7, 2005


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