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Elizabeth W. Newcomb, M. Aktar Ali, Tona Schnee, Li Lan, Yevgeniy Lukyanov, Mary Fowkes, Douglas C. Miller, David Zagzag, Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1α expression in human glioma cells by a proteasome-independent pathway: Implications for in vivo therapy, Neuro-Oncology, Volume 7, Issue 3, July 2005, Pages 225–235, https://doi.org/10.1215/S1152851704000997
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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)-1α, 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-1α 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-1α expression in the presence of a proteasome inhibitor, an agent that normally results in the accumulation and overexpression of HIF-1α. The potential to downregulate HIF-1α 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.
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Author notes
Department of Pathology (E.W.N., M.A.A., T.S., L.L., Y.L., M.F., D.C.M., D.Z.);Division of Neuropathology and Department of Neurosurgery (D.C.M., D.Z.);New York University Cancer Institute (E.W.N., D.C.M., D.Z.), New York University School of Medicine, New York, NY 10016, USA
- angiogenesis
- cytokine
- vascular endothelial growth factor a
- endothelial cells
- hypoxia
- angiogenesis inhibitors
- bodily secretions
- cell lines
- genes
- glioma
- neoplasm metastasis
- neoplasms
- transcription factor
- tumor cells
- flavopiridol
- tumor growth
- cyclin-dependent kinase inhibitors
- multicatalytic endopeptidase complex
- protein overexpression
- tumor progression
- proteasome inhibitors
- tumor cells, malignant