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  • br Tumours were harvested homogenized and the levels


    Tumours were harvested, homogenized, and the levels of down-stream protein targets of the drug were analysed using western blotting to further examine target modulation in vivo. As shown in Fig. 6, the level of the epithelial marker E-cadherin was increased, while the levels of the mesenchymal markers Vimentin and N-cadherin were decreased by the apatinib treatment. Moreover, the level of the transcription factor Snail was also decreased by the apatinib treatment. Thus, apatinib in-hibits the EMT in mice with ovarian cancer.
    4. Discussion
    As Judah Folkman first proposed in 1971, tumour growth depends on angiogenesis [11]. Inhibitors of angiogenesis have become an impor-tant therapeutic strategy in the treatment of various tumours. Tumour angiogenesis plays an important role in the occurrence, development, and metastasis of ovarian cancer. Apatinib is a small-molecule VEGFR TKI that tightly binds and inhibits VEGFR-2 [5]. It is now recognized as a first generation oral anti-angiogenesis drug in China, where it is also a potential new third-line option for treating refractory gastric cancer [12]. Currently, the definitive efficacy of apatinib cannot be estimated due to an insufficient number of patients recruited for clinical trials. However, in many pretreated patients, the survival rates, including overall survival and progression-free survival, have been improved [13]. Apatinib inhibits the migration and proliferation of endothelial Tirapazamine stimulated by VEGF. Thus, it is considered a promising VEGFR-2 in-hibitor that blocks tumour-induced angiogenesis [5,14]. The present study was performed to explore the anti-tumour activity of apatinib in ovarian cancer both in vitro and in vivo. We aimed to provide evidence supporting the use of apatinib as a treatment for ovarian cancer in clin-ical practice.
    Recent studies have reported the direct anticancer activity of apatinib in various cancer cell lines [15,16]. The proliferation of colon cancer cells was inhibited upon treatment with different concentrations of apatinib (20 and 40 μM) [17]. According to the results of the MTT pro-liferation assay, significantly lower viability of melanoma MUM-2B cells is observed in apatinib-treated groups [18]. In another study, when HCT116 and SW480 cells were treated with 20 μM apatinib, the apopto-sis percentages were 3.7% and 5.8%, respectively. As the drug concentra-tion increased to 40 μΜ, the apoptosis percentages increased to 11.9% and 13.5%. Moreover, the cell cycle was also altered [17]. However, in 
    our study, we did not observe cytotoxic effects of apatinib on ovarian cancer cells. The inhibitory mechanism of apatinib in ovarian cancer cells was further investigated by detecting changes in the cell cycle and cell apoptosis. But, in our study, apatinib did not alter the ovarian cancer cell cycle or cell apoptosis.
    In this study, apatinib substantially inhibited the migration and invasion of ovarian cancer cells. (1) Tumour cell motility is an essen-tial factor for tumour invasion and metastasis, and the JAK-STAT3 signalling pathway is commonly over-activated in many physiologi-cal cellular pathways involving cell motility [19]. Accordingly, the JAK-STAT3 signalling pathway plays an important role in cell adhe-sion, migration and other processes. (2) Tumour angiogenesis refers to the growth of capillaries induced by tumour cells and the estab-lishment of blood circulation in tumours. According to previous studies [20,21], STAT3 directly regulates the transcription of VEGF, and the persistent overactivation of the JAK-STAT3 signalling path-way in tumour cells therefore promotes tumour angiogenesis through VEGF, thereby resulting in tumour invasion and metastasis.