Abstract
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, decreased angiogenesis, as well as induced HCC apoptosis (in some tumors), and thus prolonged animal survival in a mouse xenograft model of human HCC. Our findings suggested that apatinib is a highly potent, oral active anti‐angiogenic, and anti‐HCC agent. The results from current study provide a clear biological rationale to evaluate apatinib as a new agent in HCC in clinical setting, especially for the VEGFR‐2 overexpression ones.
Highlights
Liver cancer is one of the most frequently occurring malignancies worldwide, with an estimated 0.78 million new cases each year, ranking fifth in males and ninth in females during 2012.1 liver cancer is the second leading cause of cancer-related mortality, with an estimated 0.75 million deaths globally, only behind lung cancer.[1]
This study is designed to evaluate the activity of apatinib on both human umbilical vein vascular endothelial cells (HUVECs) and Hepatocellular carcinoma (HCC) cell lines, and to investigate the characteristics and possible mechanisms underlying these effects by molecular biology methods
This study is designed to evaluate the effects of apatinib on human umbilical vein vascular endothelial cells (HUVECs) and HCC cell lines both in vivo and in vitro, as well as to investigate the characteristics and possible mechanisms underlying these effects
Summary
Liver cancer is one of the most frequently occurring malignancies worldwide, with an estimated 0.78 million new cases each year, ranking fifth in males and ninth in females during 2012.1 liver cancer is the second leading cause of cancer-related mortality, with an estimated 0.75 million deaths globally, only behind lung cancer.[1]. Liver transplantation, and local ablation are potentially curative treatments for HCC patients, with 5- year survival rates of 60%-8 0% in resection and 40%-7 0% in ablation.[8,9]. The overexpression of VEGF in tumor tissues can be used as a prognostic factor in patients with HCC after treatment.[14]. As one of the latest orally antiangiogenic agents, apatinib shows encouraging preclinical and clinical results in the treatment of various solid tumors.[16-21]. It has been approved for advanced gastric cancer after second-line chemotherapy by China Food and Drug Administration.[17]. This study is designed to evaluate the effects of apatinib on human umbilical vein vascular endothelial cells (HUVECs) and HCC cell lines both in vivo and in vitro, as well as to investigate the characteristics and possible mechanisms underlying these effects. The results are expected to provide experimental data and theoretical basis for the anti-HCC clinical practice
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