State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Exp Mol Med. 2011 Mar 31;43(3):146-52. doi: 10.3858/emm.2011.43.3.017.
Our previous report has demonstrated that 5-formylhonokiol (FH), a derivative of honokiol (HK), exerts more potent anti-proliferative activities than honokiol in several tumor cell lines. In present study, we first explored the antiangiogenic activities of 5-formylhonokiol on proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) for the first time in vitro. Then we investigated the in vivo antiangiogenic effect of 5-formylhonokiol on zebrafish angiogenesis model. In order to clarify the underlying molecular mechanism of 5-formylhonokiol, we investigated the signaling pathway involved in controlling the angiogenesis process by western blotting assay. Wound-healing results showed that 5-formylhonokiol significantly and dose-dependently inhibited migration of cultured human umbilical vein enthothelial cells. The invasiveness of HUVEC cells was also effectively suppressed at a low concentration of 5-formylhonokiol in the transwell assay. Further F-actin imaging revealed that inhibitory effect of 5-formylhonokiol on invasion may partly contribute to the disruption of assembling stress fiber. Tube formation assay, which is associated with endothelial cells migration, further confirmed the anti-angiogenesis effect of 5-formylhonokiol. In in vivo zebrafish angiogenesis model, we found that 5-formylhonokiol dose-dependently inhibited angiogenesis. Furthermore, western blotting showed that 5-formylhonokiol significantly down-regulated extracellular signal-regulated kinase (ERK) expression and inhibited the phosphorylation of ERK but not affecting the total protein kinase B (Akt) expression and related phosphorylation, suggesting that 5-formylhonokiol might exert anti-angiogenesis capacity via down-regulation of the ERK signal pathway. Taken together, these data suggested that 5-formylhonokiol might be a viable drug candidate in antiangiogenesis and anticancer therapies.
我们之前的报告表明，5-甲酰基厚朴酚（FH）是厚朴酚（HK）的衍生物，在几种肿瘤细胞系中比厚朴酚具有更强的抗增殖活性。在本研究中，我们首次探讨了 5-甲酰基厚朴酚对人脐静脉内皮细胞（HUVEC）增殖、迁移和管状形成的体外抗血管生成活性。然后，我们在斑马鱼血管生成模型中研究了 5-甲酰基厚朴酚的体内抗血管生成作用。为了阐明 5-甲酰基厚朴酚的潜在分子机制，我们通过 Western blot 分析研究了参与控制血管生成过程的信号通路。划痕实验结果表明，5-甲酰基厚朴酚显著且呈剂量依赖性地抑制培养的人脐静脉内皮细胞的迁移。在 Transwell 实验中，低浓度的 5-甲酰基厚朴酚也能有效抑制 HUVEC 细胞的侵袭。进一步的 F-肌动蛋白成像显示，5-甲酰基厚朴酚对侵袭的抑制作用可能部分归因于组装应激纤维的破坏。与内皮细胞迁移相关的管状形成实验进一步证实了 5-甲酰基厚朴酚的抗血管生成作用。在体内斑马鱼血管生成模型中，我们发现 5-甲酰基厚朴酚呈剂量依赖性抑制血管生成。此外，Western blot 显示 5-甲酰基厚朴酚显著下调细胞外信号调节激酶（ERK）表达并抑制 ERK 的磷酸化，但不影响总蛋白激酶 B（Akt）表达及其相关磷酸化，提示 5-甲酰基厚朴酚可能通过下调 ERK 信号通路发挥抗血管生成作用。综上所述，这些数据表明 5-甲酰基厚朴酚可能是一种有前途的抗血管生成和抗癌治疗候选药物。
