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A novel 2-aminobenzimidazole-based compound Jzu 17 exhibits anti-angiogenesis effects by targeting VEGFR-2 signalling.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2019 Oct; Vol. 176 (20), pp. 4034-4049. Date of Electronic Publication: 2019 Sep 15. - Publication Year :
- 2019
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Abstract
- Background and Purpose: 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.<br />Experimental Approach: 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.<br />Key Results: 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.<br />Conclusions and Implications: 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.<br /> (© 2019 The British Pharmacological Society.)
- Subjects :
- Angiogenesis Inhibitors chemistry
Animals
Antineoplastic Agents chemistry
Cell Movement drug effects
Cell Proliferation drug effects
Cells, Cultured
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Human Umbilical Vein Endothelial Cells drug effects
Humans
Lung Neoplasms metabolism
Lung Neoplasms secondary
Male
Melanoma metabolism
Melanoma pathology
Mice
Mice, Inbred C57BL
Molecular Docking Simulation
Molecular Structure
Neovascularization, Pathologic drug therapy
Neovascularization, Pathologic metabolism
Neovascularization, Pathologic pathology
Protein Kinase Inhibitors chemistry
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 metabolism
Angiogenesis Inhibitors pharmacology
Antineoplastic Agents pharmacology
Lung Neoplasms drug therapy
Melanoma drug therapy
Protein Kinase Inhibitors pharmacology
Signal Transduction drug effects
Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 176
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 31368127
- Full Text :
- https://doi.org/10.1111/bph.14813