1. Scopoletin, an active principle of tree tobacco (Nicotiana glauca) inhibits human tumor vascularization in xenograft models and modulates ERK1, VEGF-A, and FGF-2 in computer model.
- Author
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Tabana YM, Hassan LE, Ahamed MB, Dahham SS, Iqbal MA, Saeed MA, Khan MS, Sandai D, Majid AS, Oon CE, and Majid AM
- Subjects
- Angiogenesis Inhibitors isolation & purification, Angiogenesis Inhibitors metabolism, Animals, Antineoplastic Agents, Phytogenic isolation & purification, Antineoplastic Agents, Phytogenic metabolism, Cell Proliferation drug effects, Colorectal Neoplasms blood supply, Colorectal Neoplasms enzymology, Colorectal Neoplasms pathology, Dose-Response Relationship, Drug, Female, Fibroblast Growth Factor 2 chemistry, HCT116 Cells, Human Umbilical Vein Endothelial Cells drug effects, Human Umbilical Vein Endothelial Cells metabolism, Humans, Mice, Nude, Microvessels drug effects, Microvessels pathology, Mitogen-Activated Protein Kinase 3 chemistry, Neovascularization, Pathologic, Phytotherapy, Plants, Medicinal, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, Protein Conformation, Rats, Sprague-Dawley, Scopoletin isolation & purification, Scopoletin metabolism, Signal Transduction drug effects, Structure-Activity Relationship, Time Factors, Tumor Burden drug effects, Vascular Endothelial Growth Factor A chemistry, Xenograft Model Antitumor Assays, Angiogenesis Inhibitors pharmacology, Antineoplastic Agents, Phytogenic pharmacology, Colorectal Neoplasms drug therapy, Fibroblast Growth Factor 2 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Models, Biological, Molecular Docking Simulation, Scopoletin pharmacology, Nicotiana chemistry, Vascular Endothelial Growth Factor A metabolism
- Abstract
We recently reported the antineovascularization effect of scopoletin on rat aorta and identified its potential anti-angiogenic activity. Scopoletin could be useful as a systemic chemotherapeutic agent against angiogenesis-dependent malignancies if its antitumorigenic activity is investigated and scientifically proven using a suitable human tumor xenograft model. In the present study, bioassay-guided (anti-angiogenesis) phytochemical investigation was conducted on Nicotiana glauca extract which led to the isolation of scopoletin. Further, anti-angiogenic activity of scopoletin was characterized using ex vivo, in vivo and in silico angiogenesis models. Finally, the antitumorigenic efficacy of scopoletin was studied in human colorectal tumor xenograft model using athymic nude mice. For the first time, an in vivo anticancer activity of scopoletin was reported and characterized using xenograft models. Scopoletin caused significant suppression of sprouting of microvessels in rat aortic explants with IC50 (median inhibitory concentration) 0.06μM. Scopoletin (100 and 200mg/kg) strongly inhibited (59.72 and 89.4%, respectively) vascularization in matrigel plugs implanted in nude mice. In the tumor xenograft model, scopoletin showed remarkable inhibition on tumor growth (34.2 and 94.7% at 100 and 200mg/kg, respectively). Tumor histology revealed drastic reduction of the extent of vascularization. Further, immunostaining of CD31 and NG2 receptors in the histological sections confirmed the antivascular effect of scopoletin in tumor vasculature. In computer modeling, scopoletin showed strong ligand affinity and binding energies toward the following angiogenic factors: protein kinase (ERK1), vascular endothelial growth factor A (VEGF-A), and fibroblast growth factor 2 (FGF-2). These results suggest that the antitumor activity of scopoletin may be due to its strong anti-angiogenic effect, which may be mediated by its effective inhibition of ERK1, VEGF-A, and FGF-2., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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