Apatinib targets both tumor and endothelial cells in hepatocellular carcinoma

作者：Chaoxu Yang, Shukui Qin · 发表于：Cancer Medicine · 年份：2018 · DOI：10.1002/cam4.1664 · 被引用次数：74 · 研究领域：Hepatocellular Carcinoma Treatment and Prognosis、Cancer Mechanisms and Therapy、Angiogenesis and VEGF in Cancer

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed malignancies worldwide with poor prognosis and tends to be hypervascular. Aberrant expression of the vascular endothelial growth factor 2 (VEGFR-2) has been implicated in the progression of HCC and represents a valid target for anticancer therapy. Apatinib, a small molecule inhibitor of VEGFR-2 tyrosine kinase, shows strong antitumor activity in various tumors. This study is designed to evaluate the activity of apatinib on both human umbilical vein vascular endothelial cells (HUVECs) and HCC cell lines (in vitro and in vivo), and also to investigate the characteristics and possible mechanisms underlying these effects by molecular biology methods. Following the results in our study, apatinib inhibited phosphorylation of VEGFR-2 in HUVECs and blocked in vitro endothelial cell migration and tube formation. Concentration-dependent antiproliferative effects of apatinib were also observed in all 6 HCC cell lines including SK-Hep-1, HepG2, Hep3B, Huh-7, PLC/PRF/5, SMMC-7721. Moreover, response to apatinib of HCC cell lines was significantly correlated with VEGFR-2 expression level. Additionally, apatinib significantly inhibit VEGF-triggered VEGFR-2 phosphorylation and activation of downstream signaling molecules such as Akt and ERK1/2 in HCCs. Apatinib can also induce a cell cycle arrest at G2/M phase and promote HCC apoptosis tested in vitro. In vivo data showed that apatinib can effectively inhibit tumor growth, ...