title: Blockade of vascular endothelial growth factor receptors by tivozanib has potential anti-tumour effects on human glioblastoma cells.
abstract: Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C. Moreover, tivozanib decreased adhesive potential of these cells through reduction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Tivozanib diminished GBM cell invasion through impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2). Combination of tivozanib with EGFR small molecule inhibitor gefitinib synergistically increased sensitivity to gefitinib. Altogether, these findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro. Further in vivo studies are warranted to explore the anti-tumour activity of tivozanib in combinatorial approaches in GBM.
authors.affiliation: Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Majid
authors.initials: M
authors.lastname: Momeny
authors.affiliation: Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Farima
authors.initials: F
authors.lastname: Moghaddaskho
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Narges K
authors.initials: NK
authors.lastname: Gortany
authors.affiliation: Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Hassan
authors.initials: H
authors.lastname: Yousefi
authors.affiliation: Deparmtent of Pathology, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Sabourinejad
authors.affiliation: Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Zarrinrad
authors.affiliation: Department of Molecular Systems Biology, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, Tehran, Iran.
authors.forename: Shahab
authors.initials: S
authors.lastname: Mirshahvaladi
authors.affiliation: Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Haniyeh
authors.initials: H
authors.lastname: Eyvani
authors.affiliation: Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Farinaz
authors.initials: F
authors.lastname: Barghi
authors.affiliation: Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Leila
authors.initials: L
authors.lastname: Ahmadinia
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Ghazi-Khansari
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Dehpour
authors.affiliation: Cancer Biology Research Centre, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Saeid
authors.initials: S
authors.lastname: Amanpour
authors.affiliation: Deparmtent of Pathology, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Seyyed M
authors.initials: SM
authors.lastname: Tavangar
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Dardaei
authors.affiliation: Division of Oncology, Department of Internal Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Amir H
authors.initials: AH
authors.lastname: Emami
authors.affiliation: Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Kamran
authors.initials: K
authors.lastname: Alimoghaddam
authors.affiliation: Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ardeshir
authors.initials: A
authors.lastname: Ghavamzadeh
authors.affiliation: Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Seyed H
authors.initials: SH
authors.lastname: Ghaffari
mesh_terms: D023102:Anoikis; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000150:complications / Q000188:drug therapy*; D002448:Cell Adhesion; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000077156:Gefitinib; D005909:Glioblastoma / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000150:complications / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011799:Quinazolines; D011804:Quinolines; C553176:tivozanib; D040262:Receptors, Vascular Endothelial Growth Factor; D000077156:Gefitinib