Ferulic Acid Exerts Anti-Angiogenic and Anti-Tumor Activity by Targeting Fibroblast Growth Factor Receptor 1-Mediated Angiogenesis.
Ferulic Acid Exerts Anti-Angiogenic and Anti-Tumor Activity by Targeting Fibroblast Growth Factor Receptor 1-Mediated Angiogenesis.
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DOI：
10.3390/ijms161024011
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发表时间：
2015-10-12
影响因子：
5.6
通讯作者：
Lu WQ
中科院分区：
文献类型：
--
作者：
Yang GW;Jiang JS;Lu WQ
目前正在评估的大多数抗血管生成疗法靶向血管内皮生长因子（VEGF）通路;然而，肿瘤血管系统可以通过转移到其他血管生成机制来获得对VEGF靶向疗法的抗性。因此，需要评估其他阻断非VEGF血管生成途径的治疗药物。在这里，我们确定了阿魏酸作为一种新的成纤维细胞生长因子受体1（FGFR 1）抑制剂和一种新的代理具有潜在的抗血管生成和抗癌活性。阿魏酸表现出对碱性成纤维细胞生长因子1（FGF 1）的内皮细胞增殖、迁移和管形成的抑制作用。在体外和体内血管生成试验中，阿魏酸抑制FGF 1诱导的大鼠主动脉环微血管出芽和血管生成。为了理解潜在的分子基础，我们检测了阿魏酸对不同分子组分的影响，发现阿魏酸抑制FGF 1触发的FGFR 1和磷脂酰肌醇3-激酶（PI 3 K）-蛋白激酶B（Akt）信号转导的激活。阿魏酸可直接抑制黑色素瘤细胞增殖，阻断PI 3 K-Akt通路。在体内，使用黑色素瘤异种移植模型，阿魏酸显示出与抑制血管生成相关的生长抑制活性。总之，我们的结果表明，阿魏酸靶向FGFR 1介导的PI 3 K-Akt信号通路，导致黑色素瘤生长和血管生成的抑制。
Most anti-angiogenic therapies currently being evaluated target the vascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here, we identified ferulic acid as a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor and a novel agent with potential anti-angiogenic and anti-cancer activities. Ferulic acid demonstrated inhibition of endothelial cell proliferation, migration and tube formation in response to basic fibroblast growth factor 1 (FGF1). In ex vivo and in vivo angiogenesis assays, ferulic acid suppressed FGF1-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of ferulic acid on different molecular components and found that ferulic acid suppressed FGF1-triggered activation of FGFR1 and phosphatidyl inositol 3-kinase (PI3K)-protein kinase B (Akt) signaling. Moreover, ferulic acid directly inhibited proliferation and blocked the PI3K-Akt pathway in melanoma cell. In vivo, using a melanoma xenograft model, ferulic acid showed growth-inhibitory activity associated with inhibition of angiogenesis. Taken together, our results indicate that ferulic acid targets the FGFR1-mediated PI3K-Akt signaling pathway, leading to the suppression of melanoma growth and angiogenesis.