Morelloflavone, a biflavonoid, inhibits tumor angiogenesis by targeting rho GTPases and extracellular signal-regulated kinase signaling pathways.
Morelloflavone, a biflavonoid, inhibits tumor angiogenesis by targeting rho GTPases and extracellular signal-regulated kinase signaling pathways.
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DOI：
10.1158/0008-5472.can-08-2531
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发表时间：
2009-01-15
期刊：
影响因子：
11.2
通讯作者：
Liu M
中科院分区：
文献类型：
--
作者：
Pang X;Yi T;Yi Z;Cho SG;Qu W;Pinkaew D;Fujise K;Liu M
Morellofavone是从藤黄中提取的一种双黄酮，具有抗氧化、抗病毒和抗炎的特性。然而，迄今为止，该化合物在癌症治疗和肿瘤血管生成中的功能和机制尚未阐明。在这项研究中，我们假设莫瑞洛黄酮可能具有抑制血管生成的能力，血管生成是肿瘤生长、侵袭和转移的关键步骤。我们证明，莫瑞洛黄酮可以抑制血管内皮生长因子（VEGF）诱导的细胞增殖，迁移，侵袭，和毛细血管样管形成的原代培养的人脐静脉内皮细胞（HUVECs）的剂量依赖性的方式。Morelloflavone有效地抑制大鼠主动脉环试验中内皮细胞的微血管发芽和小鼠Matrigel plug试验中VEGF诱导的新血管形成。此外，Morellofavone还能抑制前列腺癌细胞（PC-3）在小鼠移植瘤模型中的肿瘤生长和肿瘤血管生成，提示Morellofavone通过靶向血管生成抑制肿瘤发生。为了了解莫瑞洛黄酮对肿瘤生长和血管生成的抑制作用的潜在机制，我们证明莫瑞洛黄酮可以抑制RhoA和Rac 1 GTP酶的激活，但对Cdc 42 GTP酶的激活几乎没有影响。此外，莫瑞洛黄酮抑制Raf/MEK/ERK途径激酶的磷酸化和活化，而不影响VEGFR 2活性。总之，我们的研究结果表明，morelloflavone发挥抗血管生成的作用，通过靶向激活Rho-GTPases和ERK信号通路。这些发现首次揭示了莫瑞洛黄酮在肿瘤血管生成中的新功能及其抗癌作用的分子基础。
Morelloflavone, a biflavonoid extracted from Garcinia dulcis, has shown anti-oxidative, antiviral, and anti-inflammatory properties. However, the function and the mechanism of this compound in cancer treatment and tumor angiogenesis have not been elucidated to date. In this study, we postulated that morelloflavone might have the ability to inhibit angiogenesis, the pivotal step in tumor growth, invasiveness and metastasis. We demonstrated that morelloflavone could inhibit vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, invasion, and capillary-like tube formation of primary cultured human umbilical endothelial cells (HUVECs) in a dose-dependent manner. Morelloflavone effectively inhibited microvessel sprouting of endothelial cells in the rat aortic ring assay and the formation of new blood microvessels induced by VEGF in the mouse Matrigel plug assay. Furthermore, morelloflavone inhibited tumor growth and tumor angiogenesis of prostate cancer cells (PC-3) in xenograft mouse tumor model in vivo, suggesting that morelloflavone inhibited tumorigenesis by targeting angiogenesis. To understand the underlying mechanism of morelloflavone on the inhibitory effect of tumor growth and angiogenesis, we demonstrated that morelloflavone could inhibit the activation of both RhoA and Rac1 GTPases, but have little effect on the activation of Cdc42 GTPase. Additionally, morelloflavone inhibited the phosphorylation and activation of Raf/MEK/ERK pathway kinases without affecting VEGFR2 activity. Together, our results indicate that morelloflavone exerts anti-angiogenic action by targeting the activation of Rho-GTPases and ERK signaling pathways. These findings are the first to reveal the novel functions of morelloflavone in tumor angiogenesis and its molecular basis for the anticancer action.