Paeonol Exerts Anti-angiogenic and Anti-metastatic Activities through Downmodulation of Akt Activation and Inactivation of Matrix Metalloproteinases
Paeonol Exerts Anti-angiogenic and Anti-metastatic Activities through Downmodulation of Akt Activation and Inactivation of Matrix Metalloproteinases
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DOI：
10.1248/bpb.32.1142
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发表时间：
2009-07-01
影响因子：
2
通讯作者：
Kim, Sung-Hoon
中科院分区：
文献类型：
--
作者：
Kim, Seung-Ae;Lee, Hyo-Jeong;Kim, Sung-Hoon
已知双羟异黄酮醇（2 '-羟基-4'-甲氧基苯乙酮）具有抗炎和抗增殖活性。最近有证据表明，抗炎剂可能是有用的设置血管生成相关的疾病。因此，本研究从体内外两方面探讨丹皮酚的抗血管生成作用及其机制。丹皮酚显著抑制碱性成纤维细胞生长因子（bFGF）刺激的人脐静脉内皮细胞（HUVECs）的增殖。在体外培养中，丹皮酚还显著抑制bFGF刺激的HUVECs的迁移和管形成。此外，丹皮酚显着抑制bFGF处理的鸡胚绒毛尿囊膜（CAM）上的新血管形成，并破坏bFGF诱导的体内基质胶塞试验中的新血管形成。此外，丹皮酚下调bFGF刺激的HUVECs中Akt磷酸化，并降低HT 1080人纤维肉瘤细胞中基质金属蛋白酶-2和-9的表达。Akt抑制剂LY 294002协同增强丹皮酚诱导的bFGF处理的HUVEC中Akt和血管内皮生长因子的失活。综上所述，这些发现表明丹皮酚可以部分通过抑制Akt信号通路和基质金属蛋白酶活性而成为血管生成和转移的有效抑制剂。
Paeonol (2'-hydroxy-4'-methoxyacetophenone) is known to possess anti-inflammatory and anti-proliferative activities. Recently there is evidence that anti-inflammatory agents may be useful in the setting of angiogenesis-related diseases. Thus in the present study the anti-angiogenic activity of paeonol and its mechanism were investigated in vitro and in vivo. Paeonol significantly inhibited proliferation of basic fibroblast growth factor (bFGF)stimulated human umbilical vein endothelial cells (HUVECs). Paeonol also significantly inhibited migration and tube formation of bFGF-stimulated HUVECs in vitro. In addition, paeonol significantly suppressed neovessel formation on bFGF-treated chick chorioallantoic membrane (CAM) and disrupted bFGF-induced neovascularization in Matrigel plug assay in vivo. Furthermore, paeonol downregluated Akt phosphorylation in bFGF-stimulated HUVECs and reduced expression of matrix metalloproteinases-2 and -9 in HT1080 human fibrosarcoma cells. The Akt inhibitor LY294002 synergistically potentiated paeonol-induced inactivation of Akt and vascular endothelial growth factor in bFGF-treated HUVECs. Taken together, these findings suggest that paeonol can be a potent suppressor of angiogenesis and metastasis partially through inhibition of Akt signaling pathway and matrix metalloproteinase activity.