Noscapine inhibits hypoxia-mediated HIF-1α expression and angiogenesis in vitro

A novel function for an old drug

Elizabeth W. Newcomb, Yevgeniy Lukyanov, Tona Schnee, M. Aktar Ali, Li Lan, David Zagzag

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Overexpression of hypoxia-inducible factor-1 (HIF-1) is a common feature in solid malignancies related to oxygen deficiency. Since increased HIF-1 expression correlates with advanced disease stage, increased angiogenesis and poor prognosis, HIF-1 and its signaling pathway have become targets for cancer chemotherapy. In this study, we identified noscapine to be a novel small molecule inhibitor of the HIF-1 pathway based on its structure-function relationships with HIF-1 pathway inhibitors belonging to the benzylisoquinoline class of plant metabolites and/or to microtubule binding agents. We demonstrate that noscapine treatment of human glioma U87MG and T98G cell lines exposed to the hypoxic mimetic agent, CoCl2, inhibits hypoxia-mediated HIF-1α expression and transcriptional activity as measured by decreased secretion of VEGF, a HIF-1 target gene. Inhibition of hypoxia-mediated HIF-1α expression was due, in part, to its ability to inhibit accumulation of HIF-1α in the nucleus and target it for degradation via the proteasome. One mechanism of action of microtubule binding agents is their antiangiogenic activity associated with disruption of endothelial tubule formation. We show that noscapine has similar properties in vitro. Thus, noscapine may possess novel antiangiogenic activity associated with two broad mechanisms of action: first, by decreasing HIF-1α expression in hypoxic tumor cells, upregulation of target genes, such as VEGF, would be decreased concomitant with its associated angiogenic activity; second, by inhibiting endothelial cells from forming blood vessels in response to VEGF stimulation, it may limit the process of neo-vascularization, correlating with antitumor activity in vivo. For more than 75 years, noscapine has traditionally been used as an oral cough suppressant with no known toxic side effects in man. Thus, the studies reported here have found a novel function for an old drug. Given its low toxicity profile, its demonstrated antitumor activity in several animal models of cancer and its potential to inhibit the HIF-1 pathway, noscapine should be considered as an antiangiogenic chemotherapy for glioma.

Original languageEnglish (US)
Pages (from-to)1121-1130
Number of pages10
JournalInternational Journal of Oncology
Volume28
Issue number5
StatePublished - May 2006

Fingerprint

Noscapine
Hypoxia-Inducible Factor 1
Pharmaceutical Preparations
Vascular Endothelial Growth Factor A
Glioma
Microtubules
Neoplasms
Hypoxia
In Vitro Techniques
Benzylisoquinolines
Antitussive Agents
Drug Therapy
Poisons
Proteasome Endopeptidase Complex
Genes
Blood Vessels

Keywords

  • Angiogenesis
  • Glioma
  • Hypoxia-inducible factor-1α
  • Microtubules
  • Proteasome degradation pathway

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Newcomb, E. W., Lukyanov, Y., Schnee, T., Ali, M. A., Lan, L., & Zagzag, D. (2006). Noscapine inhibits hypoxia-mediated HIF-1α expression and angiogenesis in vitro: A novel function for an old drug. International Journal of Oncology, 28(5), 1121-1130.

Noscapine inhibits hypoxia-mediated HIF-1α expression and angiogenesis in vitro : A novel function for an old drug. / Newcomb, Elizabeth W.; Lukyanov, Yevgeniy; Schnee, Tona; Ali, M. Aktar; Lan, Li; Zagzag, David.

In: International Journal of Oncology, Vol. 28, No. 5, 05.2006, p. 1121-1130.

Research output: Contribution to journalArticle

Newcomb, EW, Lukyanov, Y, Schnee, T, Ali, MA, Lan, L & Zagzag, D 2006, 'Noscapine inhibits hypoxia-mediated HIF-1α expression and angiogenesis in vitro: A novel function for an old drug', International Journal of Oncology, vol. 28, no. 5, pp. 1121-1130.
Newcomb, Elizabeth W. ; Lukyanov, Yevgeniy ; Schnee, Tona ; Ali, M. Aktar ; Lan, Li ; Zagzag, David. / Noscapine inhibits hypoxia-mediated HIF-1α expression and angiogenesis in vitro : A novel function for an old drug. In: International Journal of Oncology. 2006 ; Vol. 28, No. 5. pp. 1121-1130.
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