title: 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.
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.
authors.affiliation: EMAN Research and Testing Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Pulau Pinang, Malaysia. Electronic address: Yasser.tabana@hotmail.com.
authors.forename: Yasser M
authors.initials: YM
authors.lastname: Tabana
authors.affiliation: EMAN Research and Testing Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Pulau Pinang, Malaysia.
authors.forename: Loiy Elsir A
authors.initials: LE
authors.lastname: Hassan
authors.affiliation: EMAN Biodiscoveries Sdn. Bhd. Suite 126, Level 1, EUREKA Complex, Universiti Sains Malaysia (USM) Campus, Minden 11800, Penang, Malaysia.
authors.forename: Mohamed B Khadeer
authors.initials: MB
authors.lastname: Ahamed
authors.affiliation: EMAN Research and Testing Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Pulau Pinang, Malaysia.
authors.forename: Saad S
authors.initials: SS
authors.lastname: Dahham
authors.affiliation: EMAN Biodiscoveries Sdn. Bhd. Suite 126, Level 1, EUREKA Complex, Universiti Sains Malaysia (USM) Campus, Minden 11800, Penang, Malaysia.
authors.forename: Muhammad Adnan
authors.initials: MA
authors.lastname: Iqbal
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Pulau Pinang, Malaysia.
authors.forename: Mohammed A A
authors.initials: MA
authors.lastname: Saeed
authors.affiliation: EMAN Research and Testing Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Pulau Pinang, Malaysia.
authors.forename: Md Shamsuddin S
authors.initials: MS
authors.lastname: Khan
authors.affiliation: Infectomics Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200 Bertam, Penang, Malaysia.
authors.forename: Doblin
authors.initials: D
authors.lastname: Sandai
authors.affiliation: Department of Pharmacology, Quest International University, Perak, Malaysia.
authors.forename: Aman S Abdul
authors.initials: AS
authors.lastname: Majid
authors.affiliation: Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Pulau Pinang, Malaysia.
authors.forename: Chern Ein
authors.initials: CE
authors.lastname: Oon
authors.affiliation: EMAN Research and Testing Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Pulau Pinang, Malaysia. Electronic address: aminmalikshah@gmail.com.
authors.forename: Amin Malik S A
authors.initials: AM
authors.lastname: Majid
mesh_terms: D020533:Angiogenesis Inhibitors / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000378:metabolism*; D045325:HCT116 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D048052:Mitogen-Activated Protein Kinase 3 / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D062105:Molecular Docking Simulation; D009389:Neovascularization, Pathologic; D008517:Phytotherapy; D010946:Plants, Medicinal; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011487:Protein Conformation; D017207:Rats, Sprague-Dawley; D012603:Scopoletin / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors; D014026:Nicotiana / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D048052:Mitogen-Activated Protein Kinase 3; D012603:Scopoletin
keywords: Angiogenic mitogens; Antineovascularization; Nicotiana glauca; Scopoletin; Xenograft model