title: Anti-tumour activity of tivozanib, a pan-inhibitor of VEGF receptors, in therapy-resistant ovarian carcinoma cells.
abstract: Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy. Despite initial therapeutic response, the majority of advanced-stage patients relapse and succumb to chemoresistant disease. Overcoming drug resistance is the key to successful treatment of EOC. Members of vascular endothelial growth factor (VEGF) family are overexpressed in EOC and play key roles in its malignant progression though their contribution in development of the chemoresistant disease remains elusive. Here we show that expression of the VEGF family is higher in therapy-resistant EOC cells compared to sensitive ones. Overexpression of VEGFR2 correlated with resistance to cisplatin and combination with VEGFR2-inhibitor apatinib synergistically increased cisplatin sensitivity. Tivozanib, a pan-inhibitor of VEGF receptors, reduced proliferation of the chemoresistant EOC cells through induction of G2/M cell cycle arrest and apoptotic cell death. Tivozanib decreased invasive potential of these cells, concomitant with reduction of intercellular adhesion molecule-1 (ICAM-1) and diminishing the enzymatic activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-2 (MMP-2). Moreover, tivozanib synergistically enhanced anti-tumour effects of EGFR-directed therapies including erlotinib. These findings suggest that the VEGF pathway has potential as a therapeutic target in therapy-resistant EOC and VEGFR blockade by tivozanib may yield stronger anti-tumour efficacy and circumvent resistance to EGFR-directed therapies.
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: Department of Pathology, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.|Islamic Azad University, East Tehran Branch, 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: 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: 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: 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: 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: Ensieh M
authors.initials: EM
authors.lastname: Poursani
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: Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Arash
authors.initials: A
authors.lastname: Poursheikhani
authors.affiliation: Massachusetts General Hospital Cancer Centre, Charlestown, MA, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Dardaei
authors.affiliation: Department of Haematology and Blood Banking, Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Davood
authors.initials: D
authors.lastname: Bashash
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 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 Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.|Experimental Medicine Research Centre, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Dehpour
authors.affiliation: Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Marjan
authors.initials: M
authors.lastname: Yaghmaie
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 / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D010671:Phenylurea Compounds; D011804:Quinolines; D042461:Vascular Endothelial Growth Factor A; C553176:tivozanib; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D014568:Urokinase-Type Plasminogen Activator