Abstract
e15554 Background: Apatinib, a highly selective inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), inhibits the angiogenesis of tumors. The function and mechanism of Apatinib in esophageal squamous cell carcinoma (ESCC) remains unknown. Methods: The expression of VEGFR-2 in ESCC cell lines (KYSE450, EC1, KYSE410, KYSE70) were detected by western blot. KYSE450 and EC1 cell lines were treated with Apatinib, or combined with cytotoxic drugs: paclitaxel (TAX), 5-fluorouracil (5-FU) or cisplatin (DDP) respectively. Cell proliferation was then measured using CCK-8 assay; cell apoptosis was analyzed by flow cytometry; cell migration and invasion were evaluated by wound healing and transwell assays. The expression of VEGFR-2, Bcl2, MMP-2/MMP-9, p-Akt and p-mTOR in KYSE450 and EC1 cell lines were determined by western blot. Esophageal cancer xenografts model was established and used to evaluate the antitumor effects of combination of Apatinib and cytotoxic drugs in vivo. Immunohistochemistry was used to detect the expression of Ki67, VEGFR-2 and CD31 in tumor tissues of esophageal cancer xenografts model. Results: We found that Apatinib efficiently inhibited cell growth, metastasis and activity of the Akt/mTOR pathway in ESCC cells. Western blot analysis showed that Apatinib significantly increased Bax protein levels, decreased VEGFR-2, Bcl2, MMP-2/MMP-9, p-Akt and p-mTOR protein levels in ESCC cells. Moreover, Apatinib enhanced chemosensitivity of cytotoxic drugs TAX, 5-FU and DDP by upregulating expression of Bax protein, and downregulating expression of VEGFR-2, Bcl2, MMP-2/MMP-9 protein in vitro. Compared with single agent groups, the combination of Apatinib with each chemotherapeutic drug significantly repressed tumor growth and angiogenesis through blocking the expression of Ki67, VEGFR-2 and CD31 in vivo. Conclusions: Taken together, Apatinib suppressed cell growth, migration and invasion, and promoted antitumor effect of chemotherapeutic agents in ESCC.
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