State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Av. Padre Tomás Pereira S.J., Taipa, Macao SAR, China.
J Cell Biochem. 2011 Nov;112(11):3313-21. doi: 10.1002/jcb.23257.
Traditional Chinese medicinal herbs are a rich source of compounds with reported anti-inflammatory and anti-carcinogenic effects. Growing evidence shows the codependence of chronic inflammation and angiogenesis, and the potential benefits of targeting angiogenesis in the treatment of chronic inflammation and targeting inflammation in the treatment of diseases with impaired angiogenesis. We hypothesized that the anti-inflammatory activity of the natural compounds may owe at least some of its efficacy to their anti-angiogenic activity and hence we investigated the anti-angiogenic activity of these compounds in vivo in zebrafish embryos and in vitro in human umbilical vein endothelial cells (HUVECs). Nobiletin, a polymethoxylated flavonoid from citrus fruits, showed anti-angiogenic activity in both assays. Nobiletin inhibited the formation of intersegmental vessels (ISVs) in live transgenic zebrafish embryos expressing green fluorescent protein (GFP) in the vasculature. Cell cycle analysis of dissociated zebrafish embryo cells showed that nobiletin induced G0/G1 phase accumulation in a dose-dependent manner in GFP-positive endothelial cells. Nobiletin also dose-dependently induced VEGF-A mRNA expression. In HUVECs, nobiletin inhibited endothelial cell proliferation and, to a greater extent, tube formation in a dose-dependent manner. As in the in vivo study, nobiletin induced G0/G1 cell cycle arrest in HUVECs. However, this arrest was not accompanied by an increase in apoptosis, indicating a cytostatic effect of nobiletin. This study, for the first time, identifies nobiletin as having potent anti-angiogenic activity and suggests that nobiletin has a great potential for future research and development as a cytostatic anti-proliferative agent.
中草药是具有抗炎和抗癌作用的化合物的丰富来源。越来越多的证据表明慢性炎症和血管生成之间存在相互依存关系，以及在治疗慢性炎症时靶向血管生成和在治疗血管生成受损的疾病时靶向炎症的潜在益处。我们假设天然化合物的抗炎活性至少部分归因于其抗血管生成活性，因此我们在斑马鱼胚胎体内和人脐静脉内皮细胞（HUVEC）体外研究了这些化合物的抗血管生成活性。诺必灵是一种来自柑橘类水果的多甲氧基黄酮，在这两种测定中均显示出抗血管生成活性。诺必灵抑制了表达 GFP 的转基因斑马鱼胚胎中节间血管（ISVs）的形成。分离的斑马鱼胚胎细胞的细胞周期分析表明，诺必灵以剂量依赖的方式诱导 GFP 阳性内皮细胞中 G0/G1 期积累。诺必灵还剂量依赖性地诱导 VEGF-A mRNA 表达。在 HUVEC 中，诺必灵以剂量依赖的方式抑制内皮细胞增殖，并且在更大程度上抑制管形成。与体内研究一样，诺必灵诱导 HUVEC 中的 G0/G1 细胞周期停滞。然而，这并没有伴随着细胞凋亡的增加，表明诺必灵具有细胞停滞作用。这项研究首次确定诺必灵具有强大的抗血管生成活性，并表明诺必灵作为细胞增殖抑制剂具有很大的研究和开发潜力。
