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: Majid Momeny, Zahra Sabourinejad, Ghazaleh Zarrinrad, Farima Moghaddaskho, Haniyeh Eyvani, Hassan Yousefi, Shahab Mirshahvaladi, Ensieh M Poursani, Farinaz Barghi, Arash Poursheikhani, Leila Dardaei, Davood Bashash, Mahmoud Ghazi-Khansari, Seyyed M Tavangar, Ahmad R Dehpour, Marjan Yaghmaie, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Seyed H Ghaffari
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 45954 (04 06 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28383032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• NF-kappa B
• Phenylurea Compounds
• Quinolines
• Vascular Endothelial Growth Factor A
• tivozanib
• Vascular Endothelial Growth Factor Receptor-2
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Urokinase-Type Plasminogen Activator

Topics

• Anoikis (drug effects)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Clone Cells
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• G2 Phase (drug effects)
• Humans
• NF-kappa B (metabolism)
• Neoplasm Invasiveness
• Ovarian Neoplasms (drug therapy, pathology)
• Phenylurea Compounds (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-akt (metabolism)
• Quinolines (pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• Urokinase-Type Plasminogen Activator (metabolism)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)