College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea.
Eur J Pharmacol. 2012 Feb 29;677(1-3):22-30. doi: 10.1016/j.ejphar.2011.12.012. Epub 2011 Dec 20.
Abnormal angiogenesis plays a critical role in the pathogenesis of various diseases such as cancer and chronic inflammation. A variety of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), exert their action through endothelial receptor tyrosine kinases (RTKs). The synthetic phenylpropenone derivatives, used in this study were the following: 1,3-diphenyl-propenone (DPhP), 3-phenyl-1-thiophen-2-yl-propenone (PhT2P), 3-phenyl-1-thiophen-3-yl-propenone (PhT3P) and 1-furan-2-yl-3-phenyl-propenone (FPhP). These derivatives were screened for their inhibitory effect on VEGF-induced angiogenesis in vitro using HUVECs and in vivo using chick chorioallantoic membrane (CAM). The order of anti-angiogenic activity was DPhP>FPhP>PhT3P>PhT2P. The most effective compound DPhP, also known as chalcone, showed weak VEGF receptor tyrosine kinase activity compared with the specific inhibitor, SU4312 (3-[[4-(dimethylamino)phenyl]methylene]-1,3-dihydro-2H-indol-2-one). However, DPhP also inhibited several other receptor tyrosine kinases including Tie-2, epithermal growth factor (EGF) receptor, EphB2, fibroblast growth factor (FGF) receptor 3 and insulin-like growth factor-1 (IGF-1) receptor, as revealed by a receptor tyrosine kinase array assay. In addition, the down-stream signaling, including ERK phosphorylation and NF-κB activation, after receptor activation was significantly inhibited by DPhP. Furthermore, in the HT29 human colon cancer cell-inoculated CAM assay, the tumor growth and tumor-induced angiogenesis was significantly inhibited by DPhP (10μg/ml). These results suggest that the simple flavonoid, DPhP (chalcone), has valuable potential as an antiangiogenic and anti-cancer agent, and its action is mediated through the inhibition of multi-target RTKs including VEGF receptor 2.
异常的血管生成在多种疾病的发病机制中起着关键作用，如癌症和慢性炎症。各种促血管生成因子，包括血管内皮生长因子 (VEGF)，通过内皮细胞受体酪氨酸激酶 (RTKs) 发挥作用。本研究中使用的合成苯丙烯酮衍生物如下：1,3-二苯基丙烯酮 (DPhP)、3-苯基-1-噻吩-2-基丙烯酮 (PhT2P)、3-苯基-1-噻吩-3-基丙烯酮 (PhT3P) 和 1-呋喃-2-基-3-苯基丙烯酮 (FPhP)。这些衍生物在体外使用 HUVECs 和体内使用鸡胚绒毛尿囊膜 (CAM) 筛选其对 VEGF 诱导的血管生成的抑制作用。抗血管生成活性的顺序为 DPhP>FPhP>PhT3P>PhT2P。最有效的化合物 DPhP，也称为查尔酮，与特异性抑制剂 SU4312（3-[[4-(二甲基氨基)苯基]亚甲基]-1,3-二氢-2H-吲哚-2-酮）相比，对 VEGF 受体酪氨酸激酶活性较弱。然而，DPhP 还抑制了其他几种受体酪氨酸激酶，包括 Tie-2、表皮生长因子 (EGF) 受体、EphB2、成纤维细胞生长因子 (FGF) 受体 3 和胰岛素样生长因子-1 (IGF-1) 受体，这是通过受体酪氨酸激酶阵列分析揭示的。此外，受体激活后包括 ERK 磷酸化和 NF-κB 激活在内的下游信号显著被 DPhP 抑制。此外，在 HT29 人结肠癌细胞接种的 CAM 测定中，DPhP（10μg/ml）显著抑制肿瘤生长和肿瘤诱导的血管生成。这些结果表明，简单的类黄酮 DPhP（查尔酮）具有作为抗血管生成和抗癌剂的有价值的潜力，其作用是通过抑制包括 VEGF 受体 2 在内的多种靶标 RTKs 介导的。
