School of Pharmacy, China Medical University, Taichung, Taiwan.
Department of Medical Research, Hospital of China Medical University, Taichung, Taiwan.
Br J Pharmacol. 2019 Oct;176(20):4034-4049. doi: 10.1111/bph.14813. Epub 2019 Sep 15.
Recent development in drug discovery have shown benzimidazole to be an important pharmacophore,. Benzimidazole derivatives exhibit broad-spectrum pharmacological properties including anti-microbial, anti-diabetic and anti-tumour activity. However, whether benzimidazole derivatives are effective in suppressing angiogenesis and its underlying mechanisms remain incompletely understood. In this study, we aim to characterize the anti-angiogenic mechanisms of a novel 2-aminobenzimidazole-based compound, Jzu 17, in an effort to develop novel angiogenesis inhibitor.
Effects of Jzu 17 on endothelial cell proliferation, migration, invasion, and activation of signalling molecules induced by VEGF-A, were analysed by immunoblotting, MTT, BrdU, migration, and invasion assays. We performed tube formation assay, aorta ring sprouting assay, matrigel plug assay, and a mouse model of metastasis to evaluate ex vivo and in vivo anti-angiogenic effects of Jzu 17.
Jzu 17 inhibited VEGF-A-induced cell proliferation, migration, invasion, and endothelial tube formation of HUVECs. Jzu 17 suppressed VEGF-A-induced microvessel sprouting ex vivo and attenuated VEGF-A- or tumour cell-induced neovascularization in vivo. Jzu 17 also reduced B16F10 melanoma lung metastasis. In addition, Jzu 17 inhibited the phosphorylation of VEGFR-2 and its downstream signalling molecules in VEGF-A-stimulated HUVECs. Results from computer modelling further showed that Jzu 17 binds to VEGFR-2 with high affinity.
Jzu 17 may inhibit endothelial remodelling and suppress angiogenesis through targeting VEGF-A-VEGFR-2 signalling. These results also suggest Jzu 17 as a potential lead compound and warrant the clinical development of similar agents in the treatment of cancer and angiogenesis-related diseases.
最近的药物发现进展表明苯并咪唑是一种重要的药效团。苯并咪唑衍生物表现出广泛的药理特性，包括抗微生物、抗糖尿病和抗肿瘤活性。然而，苯并咪唑衍生物是否能有效抑制血管生成及其潜在机制尚不完全清楚。在这项研究中，我们旨在研究一种新型 2-氨基苯并咪唑化合物 Jzu 17 的抗血管生成机制，以期开发新型血管生成抑制剂。
通过免疫印迹、MTT、BrdU、迁移和侵袭试验分析 Jzu 17 对 VEGF-A 诱导的内皮细胞增殖、迁移、侵袭和信号分子激活的影响。我们进行了管形成试验、主动脉环发芽试验、基质胶塞试验和小鼠转移模型，以评估 Jzu 17 的体外和体内抗血管生成作用。
Jzu 17 抑制了 VEGF-A 诱导的 HUVEC 增殖、迁移、侵袭和内皮管形成。Jzu 17 抑制了 VEGF-A 诱导的体外微血管发芽，并减弱了 VEGF-A 或肿瘤细胞诱导的体内新生血管形成。Jzu 17 还减少了 B16F10 黑色素瘤肺转移。此外，Jzu 17 抑制了 VEGF-A 刺激的 HUVEC 中 VEGFR-2 及其下游信号分子的磷酸化。计算机建模的结果进一步表明，Jzu 17 与 VEGFR-2 具有高亲和力。
Jzu 17 可能通过靶向 VEGF-A-VEGFR-2 信号通路抑制内皮重塑和血管生成。这些结果还表明 Jzu 17 可能是一种潜在的先导化合物，并值得在癌症和血管生成相关疾病的治疗中开发类似的药物。
