Luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.
Luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.
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DOI：
10.1371/journal.pone.0052279
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Shi X
中科院分区：
文献类型：
--
作者：
Pratheeshkumar P;Son YO;Budhraja A;Wang X;Ding S;Wang L;Hitron A;Lee JC;Kim D;Divya SP;Chen G;Zhang Z;Luo J;Shi X
血管生成，即在原有血管床上形成新血管，是肿瘤生长、侵袭和转移的必要条件。木犀草素是一种常见的膳食类黄酮，存在于水果和蔬菜中。我们通过体外、离体和体内模型研究了木犀草素的抗血管生成活性。体外大鼠主动脉环实验表明，无毒浓度的木犀草素显著抑制微血管的萌发和增殖、内皮细胞的迁移、侵袭和成管，这些是血管生成过程中的关键事件。鸡蛋绒毛尿囊膜实验（CAM）和基质塞实验显示木犀草素还能抑制体外血管生成。明胶酶谱分析表明木犀草素对基质金属蛋白酶MMP-2和MMP-9的活化有抑制作用。Western blot分析显示，木草素抑制VEGF诱导的huvec中VEGF受体2及其下游蛋白激酶AKT、ERK、mTOR、P70S6K、MMP-2和MMP-9的磷酸化。木犀草素可显著降低PC-3细胞中IL-1β、IL-6、IL-8、TNF-α等促炎因子水平。木犀草素（10 mg/kg/d）显著降低前列腺异种移植小鼠模型实体瘤的体积和重量，表明木犀草素通过靶向血管生成抑制肿瘤发生。CD31和CD34免疫组化染色进一步显示木犀草素能显著抑制微血管密度。木草素还能降低前列腺癌细胞的细胞活力，诱导细胞凋亡，这与下调AKT、ERK、mTOR、P70S6K、MMP-2和MMP-9的表达有关。综上所述，我们的研究结果表明木犀草素通过抑制血管内皮生长因子受体2介导的血管生成来抑制人前列腺肿瘤的生长。
Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis. Luteolin is a common dietary flavonoid found in fruits and vegetables. We studied the antiangiogenic activity of luteolin using in vitro, ex vivo, and in vivo models. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Gelatin zymographic analysis demonstrated the inhibitory effect of luteolin on the activation of matrix metalloproteinases MMP-2 and MMP-9. Western blot analysis showed that luteolin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 in HUVECs. Proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α level were significantly reduced by the treatment of luteolin in PC-3 cells. Luteolin (10 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that luteolin inhibited tumorigenesis by targeting angiogenesis. CD31 and CD34 immunohistochemical staining further revealed that the microvessel density could be remarkably suppressed by luteolin. Moreover, luteolin reduced cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 expressions. Taken together, our findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.