Anlotinib Inhibits Tumor Angiogenesis and Promotes the Anticancer Effect of Radiotherapy on Esophageal Cancer through Inhibiting EphA2

Abstract

Background Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and has antitumor activity in a variety of solid tumors. Given that, our study was designed to unearth the mechanism of anlotinib in radioresistant esophageal cancer (EC) cells. Methods Radioresistant EC cell lines TE-1R and KYSE-150R were established by multiple fractionated irradiation. Detection of cell proliferation was governed by the MTT assay, angiogenesis by the tube formation assay, and cell migration and invasion by the transwell assay. Lastly, RT-qPCR Western blotting was employed to detect the expression of related genes. Cancerous cells showing tumor growth were then detected by tumor xenografts in mice. Results Radioresistant EC cell lines TE-1R and KYSE-150R were successfully established. Anlotinib downregulated EphA2 inhibited proliferation, angiogenesis, migration, and invasion of radioresistant EC cells in vitro. The up-regulated expression of EphA2 in both EC cell lines and radioresistant EC cells, along with anlotinib, in turn, inhibited the expression of EphA2 in radioresistant EC cells. Inhibiting EphA2 also enhanced anlotinib-mediated effects on radioresistant EC cells, so as to restrain cell proliferation, angiogenesis, migration, and invasion. Correspondingly, overexpression of EphA2 is capable of reversing the therapeutic effect of anlotinib on radioresistant EC cells. Also, anlotinib enhances the inhibitory effect of irradiation on mice. Conclusion It is concluded that anlotinib inhibits EphA2 expression, thereby suppressing angiogenesis and resensitizing EC cells to radiotherapy, providing another perspective to overcome radioresistance in EC.