Abstract
Axitinib, small molecule tyrosine kinase inhibitor, demonstrates anti-cancer activity for various solid tumors. We investigated anti-cancer effect of axitinib in epithelial ovarian cancer (EOC). We treated EOC cells (A2780, HeyA8, RMG1, and HeyA8-MDR) with axitinib to evaluate its effects on cell viabilty, apoptosis and migration. Western blots were performed to assess VEGFR2, ERK, and AKT levels, and ELISA and FACS to evaluate apoptosis according to axitinib treatment. In addition, in vivo experiments in xenografts using A2780, RMG1, and HeyA8-MDR cell lines were performed. We repeated the experiment with patient-derived xenograft models (PDX) of EOC. Axitinib significantly inhibited cell survival and migration, and increased apoptosis in EOC cells. The expression of VEGFR2 and phosphorylation of AKT and ERK in A2780, RMG1, and HeyA8 were decreased with axitinib treatment in dose-dependent manner, but not in HeyA8-MDR. In in vivo experiments, axitinib significantly decreased tumor weight in xenograft models of drug-sensitive (A2780), and clear cell carcinoma (RMG1) and PDX models for platinum sensitive EOC compared to control, but was not effective in drug-resistant cell line (HeyA8-MDR) or heavily pretreated refractory PDX model. Axitinib showed significant anti-cancer effects in drug-sensitive or clear cell EOC cells via inhibition of VEGFR signals associated with cell proliferation, apoptosis and migration, but not in drug-resistant cells.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, and one of the leading causes of cancer-related death in women
Apoptosis induction measured by active caspase-3 enzyme linked immunosorbent assay (ELISA) (24 h of treatment with 0, 1, 2, and 4 uM axitinib) and annexin V- FITC incorporation after treatment with axitinib (2 nM for A2780 and 4 nM for HeyA8, HeyA8-MDR, and RMG1) resulted in significantly increased apoptosis in axitinib-treated cells compared with control (Fig. 2, p < 0.0001 for A2780, HeyA8, p = 0.0022 for HeyA8-MDR, p = 0.0043 for RMG-1, respectively)
Axitinib-induced apoptosis was confirmed in epithelial ovarian cancer (EOC) cell lines
Summary
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, and one of the leading causes of cancer-related death in women. Despite previous investigations of novel chemotherapeutic regimens, and other targeted therapies, there was no significant improvements in clinical outcomes or cure rates, with current 5-year overall survival rates of 45%1. Several target agents have reached phase 3 clinical trials for treatment of EOC2. Bevacizumab (VEGF-A-specific humanized IgG1), an antiangiogenic agent, resulted in significant improvements of progression-free survival (PFS) when combined with chemotherapeutic agents, and has become a standard therapy for EOC in selected patients[3]. Clinical studies demonstrated promising anti-cancer activity in phase 2 trials for the treatment of various solid tumors. The purpose of this study was to evaluate the anti-cancer effects of axinitib in EOC by using cell line xenografts and patient-derived xenograft (PDX) models, and to investigate the possible underlying mechanisms
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