Noscapine inhibits hypoxia-mediated HIF-1α expression andangiogenesis in vitro: a novel function for an old drug

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, CoCl 2 , inhibits hypoxia-mediated HIF-1· expression and transcriptional activity as measured by decreased secretion of VEGF, a HIF-1 target gene. Inhibition of hypoxia-mediated HIF-1· expression was due, in part, to its ability to inhibit accumulation of HIF-1· 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-1· 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.

Natural product derivative Bis(4-fluorobenzyl)trisulfide inhibits tumor growth by modification of β-tubulin at Cys 12 and suppression of microtubule dynamics

“…Inhibition of angiogenesis by disrupting microtubules has also been reported for microtubule inhibitors such as taxanes, vincristine, noscapine, and a new antimicrotubule agent, 2ME2 (34,36). Microtubule inhibition by these agents downregulates hypoxia-inducible factor-1at the posttranscriptional level and inhibits hypoxia-inducible factor-1-induced transcriptional activation of vascular endothelial growth factor expression, which plays a key role in cancer angiogenesis (34,36). It has been reported that inhibition of angiogenesis by another structurally similar natural product diallyl trisulfide resulted from inactivation of Akt and downregulation of vascular endothelial growth factor and vascular endothelial growth factor R2 (37,38).…”

“…Inhibition of angiogenesis by disrupting microtubules has also been reported for microtubule inhibitors such as taxanes, vincristine, noscapine, and a new antimicrotubule agent, 2ME2 (34,36). Microtubule inhibition by these agents downregulates hypoxia-inducible factor-1at the posttranscriptional level and inhibits hypoxia-inducible factor-1-induced transcriptional activation of vascular endothelial growth factor expression, which plays a key role in cancer angiogenesis (34,36).…”

“…The treated cells were then stained with an antibody against phosphohistone histone H3, a marker for cells undergoing mitosis and mitotic arrest (34,35). As shown in Fig.…”

Modulation of hypoxia-inducible factors (HIF) from an integrative pharmacological perspective

“…HIF protein can also be SUMOylated by ubiquitin E3 ligases that control its degradation by the ubiquitin-proteasome pathway in the human cervical cancer cell line HeLa [76]. Noscapine, another microtubule modulator agent, promotes the degradation of HIF-1a protein via the proteasome in the human glioma cell lines U87MG and T98G [77]. Noscapine acts in a similar way to the heat shock protein 90 (Hsp90) inhibitor, geldanamycin [78] by blocking the accumulation of HIF-1a protein in the nucleus [77].…”

Cyclin-dependent kinase inhibitor, P276-00, inhibits HIF-1α and induces G2/M arrest under hypoxia in prostate cancer cells

“…1,2 Overexpression of hypoxia-inducible factor-1 (HIF-1) is a common feature of solid malignancies related to oxygen deficiencies occurring through multiple mechanisms, including increasing proliferation of tumor cells, lack of oxygen diffusion, decreased blood flow and abnormal tumor vasculature. 3,4 HIF-1 is a heterodimer of a hypoxia-stabilized and activated asubunit and an oxygen-insensitive b-subunit. Therefore, the biological activity of HIF-1 is determined by HIF-1a expression.…”