Anti-tumour activity of tivozanib, a pan-inhibitor of VEGF receptors, in therapy-resistant ovarian carcinoma cells
| Autor: | Ardeshir Ghavamzadeh, Farinaz Barghi, Ghazaleh Zarrinrad, Shahab Mirshahvaladi, Ensieh M. Poursani, Davood Bashash, Kamran Alimoghaddam, Seyed H. Ghaffari, Farima Moghaddaskho, Arash Poursheikhani, Majid Momeny, Mahmoud Ghazi-Khansari, Hassan Yousefi, Seyyed Mohammad Tavangar, Haniyeh Eyvani, Marjan Yaghmaie, Leila Dardaei, Ahmad Reza Dehpour, Zahra Sabourinejad |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology G2 Phase Vascular Endothelial Growth Factor A medicine.medical_specialty Tivozanib Antineoplastic Agents Apoptosis Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine Ovarian carcinoma Cell Line Tumor Medicine Humans Apatinib Neoplasm Invasiveness Extracellular Signal-Regulated MAP Kinases Cell Proliferation Cisplatin Ovarian Neoplasms Multidisciplinary business.industry Phenylurea Compounds NF-kappa B Drug Synergism Cell Cycle Checkpoints Anoikis Urokinase-Type Plasminogen Activator Vascular Endothelial Growth Factor Receptor-2 Clone Cells Vascular endothelial growth factor 030104 developmental biology chemistry Cell culture Drug Resistance Neoplasm 030220 oncology & carcinogenesis Quinolines Female Erlotinib business Plasminogen activator Proto-Oncogene Proteins c-akt medicine.drug Signal Transduction |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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