Newcomb Elizabeth W, Lukyanov Yevgeniy, Schnee Tona, Ali M Aktar, Lan Li, Zagzag David
Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
Int J Oncol. 2006 May;28(5):1121-30.
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.
缺氧诱导因子-1（HIF-1）的过表达是实体恶性肿瘤中与缺氧相关的常见特征。由于HIF-1表达增加与疾病晚期、血管生成增加和预后不良相关，HIF-1及其信号通路已成为癌症化疗的靶点。在本研究中，基于其与属于苄基异喹啉类植物代谢产物和/或微管结合剂的HIF-1通路抑制剂的结构-功能关系，我们确定那可丁是一种新型的HIF-1通路小分子抑制剂。我们证明，用那可丁处理暴露于低氧模拟剂CoCl2的人胶质瘤U87MG和T98G细胞系，可抑制低氧介导的HIF-1α表达和转录活性，这可通过HIF-1靶基因VEGF分泌减少来衡量。低氧介导的HIF-1α表达的抑制部分归因于其抑制HIF-1α在细胞核中积累并通过蛋白酶体将其靶向降解的能力。微管结合剂的一种作用机制是其与内皮小管形成破坏相关的抗血管生成活性。我们表明那可丁在体外具有类似的特性。因此，那可丁可能具有与两种广泛作用机制相关的新型抗血管生成活性：第一，通过降低低氧肿瘤细胞中HIF-1α的表达，靶基因如VEGF的上调将与其相关的血管生成活性同时降低；第二，通过抑制内皮细胞响应VEGF刺激形成血管，它可能限制新血管形成过程，这与体内抗肿瘤活性相关。75多年来，那可丁传统上一直用作口服止咳药，在人体中没有已知的毒副作用。因此，此处报道的研究发现了一种老药的新功能。鉴于其低毒性、在几种癌症动物模型中已证明的抗肿瘤活性以及其抑制HIF-1通路的潜力，那可丁应被视为胶质瘤的抗血管生成化疗药物。
