Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1α expression in human glioma cells by a proteasome-independent pathway

Implications for in vivo therapy

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

Research output: Contribution to journalArticle

59 Citations (Scopus)

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 hypoxia-inducible 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.

Original languageEnglish (US)
Pages (from-to)225-235
Number of pages11
JournalNeuro-Oncology
Volume7
Issue number3
DOIs
StatePublished - Jul 2005

Fingerprint

alvocidib
Hypoxia-Inducible Factor 1
Proteasome Endopeptidase Complex
Glioma
Down-Regulation
Vascular Endothelial Growth Factor A
Neoplasms
Proteasome Inhibitors
Therapeutics
Cell Line
Cyclin-Dependent Kinases
Cell Movement
Hypoxia
Transcription Factors
Endothelial Cells

Keywords

  • Flavopiridol
  • Glioma
  • HIF-1α
  • Hypoxia
  • Proteasome inhibitor
  • VEGF

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1α expression in human glioma cells by a proteasome-independent pathway : Implications for in vivo therapy. / Newcomb, Elizabeth W.; Ali, M. Aktar; Schnee, Tona; Lan, Li; Lukyanov, Yevgeniy; Fowkes, Mary; Miller, Douglas C.; Zagzag, David.

In: Neuro-Oncology, Vol. 7, No. 3, 07.2005, p. 225-235.

Research output: Contribution to journalArticle

Newcomb, Elizabeth W. ; Ali, M. Aktar ; Schnee, Tona ; Lan, Li ; Lukyanov, Yevgeniy ; Fowkes, Mary ; Miller, Douglas C. ; Zagzag, David. / Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1α expression in human glioma cells by a proteasome-independent pathway : Implications for in vivo therapy. In: Neuro-Oncology. 2005 ; Vol. 7, No. 3. pp. 225-235.
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