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 relation-ships 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-1alpha expression and transcriptional activity as measured by decreased secretion of
VEGF, a HIF-1 target gene. Inhibition of
hypoxia-mediated HIF-1alpha expression was due, in part, to its ability to inhibit accumulation of HIF-1alpha 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-1alpha 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.