Nobiletin, a citrus polymethoxyflavonoid, suppresses multiple angiogenesis-related endothelial cell functions and angiogenesis in vivo
Nobiletin, a citrus polymethoxyflavonoid, suppresses multiple angiogenesis-related endothelial cell functions and angiogenesis in vivo
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DOI：
10.1111/j.1349-7006.2010.01668.x
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发表时间：
2010-11-01
期刊：
影响因子：
5.7
通讯作者：
Oikawa, Tsutomu
中科院分区：
文献类型：
--
作者：
Kunimasa, Kazuhiro;Ikekita, Masahiko;Oikawa, Tsutomu
Nobiletin是一种柑橘类多甲氧基黄酮，可抑制肿瘤生长和转移，这两者都依赖于血管生成。我们最近确定了诺贝尔作为细胞分化调节剂。由于细胞分化是血管生成中的关键事件，因此可能的是，诺必利可表现出抗血管生成活性，从而抑制这些肿瘤恶性特性。为了验证这种可能性，我们研究了在体外和体内的抗血管生成作用。诺必列汀对血管生成相关内皮细胞（EC）的多种功能具有浓度依赖性抑制作用，抑制内皮细胞生长因子（ECGS）刺激的人脐静脉EC（HUVEC）的增殖、迁移和基质胶上的管腔形成。明胶酶谱和北方印迹法显示，川陈皮素抑制ECGS刺激的HUVEC产生基质金属蛋白酶-2（pro-matrix metalloproteinase-2，MMP-2）及其mRNA表达。Nobiletin还下调细胞相关纤溶酶原激活物（PA）活性和尿激酶型PA mRNA表达。此外，在体外血管生成模型中，诺贝尔碱抑制血管内皮生长因子和FGF诱导的血管生成分化。这种抑制伴随着血管生成相关的信号分子的下调，如细胞外信号调节激酶1/2和c-Jun N-末端激酶，和转录因子（c-Jun和信号转导和转录激活因子3），以及半胱天冬酶途径的激活。在鸡胚绒毛尿囊膜试验中，川陈皮素显示出抗血管生成活性，ID 50值为每个鸡蛋10微克（24.9 nmol）。这些结果表明，川陈皮素是一种新的抗血管生成化合物，通过联合抑制多种血管生成EC功能来显示其活性。（Cancer Sci 2010; 101：2462-2469）。
Nobiletin is a citrus polymethoxyflavonoid that suppresses tumor growth and metastasis, both of which depend on angiogenesis. We recently identified nobiletin as a cell differentiation modulator. Because cell differentiation is a critical event in angiogenesis, it might be possible that nobiletin could exhibit antiangiogenic activity, resulting in suppression of these tumor malignant properties. To verify this possibility, we examined the antiangiogenic effects of nobiletin in vitro and in vivo. Nobiletin had concentration-dependent inhibitory effects on multiple functions of angiogenesis-related endothelial cells (EC); it suppressed the proliferation, migration and tube formation on matrigel of human umbilical vein EC (HUVEC) stimulated with endothelial cell growth supplement (ECGS), a mixture of acidic and basic fibroblast growth factors (FGFs). Gelatin zymography and northern blotting revealed that nobiletin suppressed pro-matrix metalloproteinase-2 (proMMP-2) production and MMP-2 mRNA expression in ECGS-stimulated HUVEC. Nobiletin also downregulated cell-associated plasminogen activator (PA) activity and urokinase-type PA mRNA expression. Furthermore, nobiletin inhibited angiogenic differentiation induced by vascular endothelial growth factor and FGF, an in vitro angiogenesis model. This inhibition was accompanied by downregulation of angiogenesis-related signaling molecules, such as extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase, and transcriptional factors (c-Jun and signal transducer and activator of transcription 3), and activation of the caspase pathway. In a chick embryo chorioallantoic membrane assay, nobiletin showed an antiangiogenic activity, the ID50 value being 10 mu g (24.9 nmol) per egg. These results indicate that nobiletin is a novel antiangiogenic compound that exhibits its activity through combined inhibition of multiple angiogenic EC functions. (Cancer Sci 2010; 101: 2462-2469).