Noscapine inhibits hypoxia-mediated HIF-1alpha expression andangiogenesis in vitro: a novel function for an old drug.
Noscapine inhibits hypoxia-mediated HIF-1alpha expression andangiogenesis in vitro: a novel function for an old drug.
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DOI：
10.3892/ijo.28.5.1121
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发表时间：
2006-05
影响因子：
5.2
通讯作者：
E. Newcomb;Yevgeniy Lukyanov;Tona Schnee;M. Ali;L. Lan;D. Zagzag
中科院分区：
文献类型：
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作者：
E. Newcomb;Yevgeniy Lukyanov;Tona Schnee;M. Ali;L. Lan;D. Zagzag
缺氧诱导因子-1(HIF-1)的过度表达是与缺氧相关的实体恶性肿瘤的常见特征。由于HIF-1的高表达与疾病的进展、血管生成增加及预后不良有关，HIF-1及其信号通路已成为肿瘤化疗的靶点。在本研究中，我们根据诺斯卡因与植物代谢产物中的苄基异喹啉类HIF-1途径抑制剂和/或微管结合剂之间的构效关系，确定它是一种新的HIF-1途径的小分子抑制剂。我们证明，诺斯汀治疗暴露于低氧模拟剂CoCl2的人胶质瘤U87 MG和T98G细胞株，通过减少HIF-1靶基因VEGF的分泌来抑制缺氧介导的HIF-1α的表达和转录活性。抑制低氧介导的HIF-1α表达的部分原因是它能够抑制HIF-1α在细胞核内的积聚，并通过蛋白酶体将其靶向降解。微管结合剂的作用机制之一是它们与破坏内皮管形成相关的抗血管生成活性。我们发现诺斯卡因在体外也有类似的性质。因此，诺斯汀可能具有新的抗血管生成活性，可能与两个广泛的作用机制有关：第一，通过减少缺氧肿瘤细胞中HIF-1α的表达，靶基因如血管内皮生长因子的上调将减少，同时伴随着其相关的血管生成活性；第二，通过抑制血管内皮细胞对血管生成的刺激，它可能限制与体内抗肿瘤活性相关的新生血管形成过程。75多年来，诺斯汀一直被用作口服止咳药，在人类身上没有已知的毒副作用。因此，这里报道的研究发现了一种旧药物的新功能。考虑到它的低毒特性，它在几种癌症动物模型中显示了抗肿瘤活性，以及它抑制HIF-1途径的潜力，诺斯汀应该被认为是一种抗胶质瘤血管生成的化疗药物。
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.