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

• Published in: Microvascular research 2016-09, Vol.107, p.17-33
• Main Authors: Tabana, Yasser M., Hassan, Loiy Elsir A., Ahamed, Mohamed B. Khadeer, Dahham, Saad S., Iqbal, Muhammad Adnan, Saeed, Mohammed A.A., Khan, Md Shamsuddin S., Sandai, Doblin, Majid, Aman S. Abdul, Oon, Chern Ein, Majid, Amin Malik S.A.
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - isolation & purification; Angiogenesis Inhibitors - metabolism; Angiogenesis Inhibitors - pharmacology; Angiogenic mitogens; Animals; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - metabolism; Antineoplastic Agents, Phytogenic - pharmacology; Antineovascularization; Cell Proliferation - drug effects; Colorectal Neoplasms - blood supply; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - pathology; Dose-Response Relationship, Drug; Female; Fibroblast Growth Factor 2 - chemistry; Fibroblast Growth Factor 2 - metabolism; 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; Mitogen-Activated Protein Kinase 3 - metabolism; Models, Biological; Molecular Docking Simulation; Neovascularization, Pathologic; Nicotiana - chemistry; Nicotiana glauca; Phytotherapy; Plants, Medicinal; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Protein Conformation; Rats, Sprague-Dawley; Scopoletin; Scopoletin - isolation & purification; Scopoletin - metabolism; Scopoletin - pharmacology; Signal Transduction - drug effects; Structure-Activity Relationship; Time Factors; Tumor Burden - drug effects; Vascular Endothelial Growth Factor A - chemistry; Vascular Endothelial Growth Factor A - metabolism; Xenograft model; Xenograft Model Antitumor Assays
• ISSN: 0026-2862; 1095-9319
• DOI: 10.1016/j.mvr.2016.04.009

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. [Display omitted] •Antiangiogenic activity of scopoletin was investigated.•Scopoletin showed suppression of tumor in xenograft models.•Antitumor effect of scopoletin is partly due to antivasularization.•Scopoletin has strong affinity for ERK1, VEGF-A, and FGF-2 in silico.•Immunostaining of CD31 and NG2 receptors confirmed the anti-vascular effect of scopoletin.