PMID- 16596228 OWN - NLM STAT- MEDLINE DCOM- 20060524 LR - 20151119 IS - 1019-6439 (Print) IS - 1019-6439 (Linking) VI - 28 IP - 5 DP - 2006 May TI - Noscapine inhibits hypoxia-mediated HIF-1alpha expression andangiogenesis in vitro: a novel function for an old drug. PG - 1121-30 AB - 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. FAU - Newcomb, Elizabeth W AU - Newcomb EW AD - Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, NY 10016, USA. newcoe01@med.nyu.edu FAU - Lukyanov, Yevgeniy AU - Lukyanov Y FAU - Schnee, Tona AU - Schnee T FAU - Ali, M Aktar AU - Ali MA FAU - Lan, Li AU - Lan L FAU - Zagzag, David AU - Zagzag D LA - eng GR - CA-100426/CA/NCI NIH HHS/United States GR - CA-90290/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - Greece TA - Int J Oncol JT - International journal of oncology JID - 9306042 RN - 0 (Angiogenesis Inhibitors) RN - 0 (DNA Primers) RN - 0 (HIF1A protein, human) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (RNA, Neoplasm) RN - 3G0H8C9362 (Cobalt) RN - 8V32U4AOQU (Noscapine) RN - EVS87XF13W (cobaltous chloride) SB - IM MH - Angiogenesis Inhibitors/*pharmacology MH - Brain Neoplasms MH - Cell Line, Tumor MH - Cobalt/pharmacology MH - DNA Primers MH - Gene Expression Regulation, Neoplastic/drug effects MH - Glioma MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/*genetics MH - Neovascularization, Pathologic/*prevention & control MH - Noscapine/*pharmacology MH - RNA, Neoplasm/genetics/isolation & purification EDAT- 2006/04/06 09:00 MHDA- 2006/05/25 09:00 CRDT- 2006/04/06 09:00 PHST- 2006/04/06 09:00 [pubmed] PHST- 2006/05/25 09:00 [medline] PHST- 2006/04/06 09:00 [entrez] PST - ppublish SO - Int J Oncol. 2006 May;28(5):1121-30.