Anti-tumour activity of tivozanib, a pan-inhibitor of VEGF receptors, in therapy-resistant ovarian carcinoma cells

Majid Momeny,Ghazaleh Zarrinrad,Seyed H Ghaffari,Arash Poursheikhani,Ahmad R Dehpour,Farima Moghaddaskho,Marjan Yaghmaie,Shahab Mirshahvaladi,Davood Bashash,Mahmoud Ghazi-Khansari,Leila Dardaei,Hassan Yousefi,Kamran Alimoghaddam,Ensieh M Poursani,Farinaz Barghi,Seyyed M Tavangar,Zahra Sabourinejad,Ardeshir Ghavamzadeh,Haniyeh Eyvani

doi:10.1038/srep45954

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.

Highlights

Intrinsic and acquired resistance to chemotherapy are responsible for treatment failure in EOC3
This screening experiment revealed that the expression of VEGFA, VEGFC, VEGFD, VEGFR type 1 (VEGFR1) and VEGFR2 is higher in multidrug-resistant OVCAR3, SKOV3 and A2780CP cells compared to the chemosensitive ones (Fig. 1A,B)
The vascular endothelial growth factor (VEGF) family is aberrantly expressed in EOC9,49

Summary

Introduction

Intrinsic and acquired resistance to chemotherapy are responsible for treatment failure in EOC3. Increased expression of VEGFC and VEGFR2 correlates with lymph node metastasis and peritoneal dissemination, a frequent cause of death in patients with primary advanced or recurrent EOC12,13. In this setting, blocking VEGFA activity in murine models of EOC halts tumour growth and ascites formation[14]. While early clinical studies have determined remarkable activity of bevacizumab, lack of improvement in overall survival, considerable toxicity, frequent development of resistance, absence of a predictive biomarker and high cost of bevacizumab therapy highlight the need to establish novel and more efficacious anti-angiogenesis therapy in EOC17,22. We examined the mechanistic activity of tivozanib in therapy-resistant EOC cell lines

Methods

Results

Conclusion