| Summary: | 博士 === 國立臺灣大學 === 藥理學研究所 === 100 === Dysregulated angiogenesis contributes to various diseases progression. Insufficient blood vessels growth causes myocardial infarction, stroke, and neuro-degeneration disorders while overgrowth or abnormal blood vessels promote malignant tumor, retinopathy and inflammatory diseases. Therefore, modulating angiogenesis processes provide a therapeutic direction for disease treatment. Tumor angiogenesis is a multistep process by which tumor cell induces new capillaries from pre-existing vessels. Vascular endothelial growth factor (VEGF) is a potent angiogenesis inducer which can be released by tumor cells. VEGF induces endothelial cell proliferation, migration and differentiation to form new vasculature for supporting tumor growth. Owing to the multi-involvement on types of cells and varieties of pro- and anti-angiogenic molecules, it reveals many target sites for the drug development. Although several anti-angiogenic drugs have been approved for eye degeneration and cancer treatments, the clinical outcomes, side effects and resistance remain challenges in these therapies.
In this report, we presented two serial derivative compounds, NP-184 and bp5250, which were screened for the inhibitory effect on angiogenesis by bioactivity assays. Both NP-184 and bp5250 inhibit the VEGF-induced proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) in a concentration- dependent manner. They also suppress the capillary sprouting from rat aortic ring ex vivo. As in vivo assay, NP-184 and bp5250 both dose-dependently repress new vessels invasion to the plugs in the VEGF induced Matrigel assay. In the VEGF activated signaling level, NP-184 reduces the phosphorylation of ERK and AKT, and NF-kappaB translocation while bp5250 decreases the activation of ERK, p38, PI3K, AKT, FAK, Src, Rac1/cdc42 and Rho. In addition, bp5250 inhibits the expression of HIF-1alfa and VEGF mRNA expression. Along with their additional antiplatelet activity, both compounds may provide additional advantages in vivo for suppression of tumor-induced angiogenesis, and hypercoagulation-induced tumor metastasis. However, detailed molecular mechanisms still need to be further investigated. Besides, optimization of the lead compounds by rational design and functional assays for improvement of potency is also required.
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