Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1693-1701. doi: 10.1016/j.bbadis.2018.02.014. Epub 2018 Feb 24.
Although apatinib has been demonstrated with potential antitumor activity in multiple solid tumors, the underlying mechanism of apatinib for the treatment of hepatocellular carcinoma (HCC) remains unclear. In the present study, we explored if there are any direct suppression effects of apatinib on HCC cells and its relevant targets. We investigated the effect of apatinib on viability of five HCC cell lines and an intrahepatic cholangiocarcinoma cell line, and colony formation, apoptosis and migration of representative HCC cells in vitro; and HCC progression in a xenograft mouse model. Using a phospho-receptor tyrosine kinase pathway array with 49 different tyrosine kinases, we screened and verified the tyrosine kinase targets involved in apatinib response. Apatinib treatment significantly inhibited HCC cell viability, proliferation, colony formation, and migration, and enhanced cell apoptosis in a concentration-dependent manner (p < 0.05). Furthermore, apatinib showed a favorable anti-tumor growth effect (71% of inhibition ratio, p < 0.05) in an established human HCC xenograft mice model with good safety. RTK pathway arrays and western blots analysis demonstrated that apatinib significantly downregulated the phosphorylation levels of several tyrosine kinase receptors, particularly PDGFR-α and IGF-IR, and inhibited Akt phosphorylation. These data suggest that the apatinib may have a direct anti-HCC effect as a direct multi-target RTK inhibitor of HCC cells and a promising potentiality in HCC clinical therapies.
虽然阿帕替尼在多种实体肿瘤中显示出潜在的抗肿瘤活性，但阿帕替尼治疗肝细胞癌（HCC）的潜在机制尚不清楚。在本研究中，我们探讨了阿帕替尼是否对 HCC 细胞及其相关靶标有直接抑制作用。我们研究了阿帕替尼对五种 HCC 细胞系和一种肝内胆管癌细胞系的活力、代表性 HCC 细胞的体外集落形成、凋亡和迁移以及异种移植小鼠模型中的 HCC 进展的影响。使用包含 49 种不同酪氨酸激酶的磷酸化受体酪氨酸激酶通路阵列，我们筛选并验证了参与阿帕替尼反应的酪氨酸激酶靶标。阿帕替尼治疗以浓度依赖性方式显著抑制 HCC 细胞活力、增殖、集落形成和迁移，并增强细胞凋亡（p<0.05）。此外，阿帕替尼在已建立的人 HCC 异种移植小鼠模型中显示出良好的抗肿瘤生长作用（抑制率为 71%，p<0.05），且安全性良好。RTK 通路阵列和 Western blot 分析表明，阿帕替尼显著下调了几种酪氨酸激酶受体的磷酸化水平，特别是 PDGFR-α 和 IGF-IR，并抑制了 Akt 的磷酸化。这些数据表明，阿帕替尼可能作为 HCC 细胞的直接多靶点 RTK 抑制剂具有直接的抗 HCC 作用，并有希望用于 HCC 的临床治疗。
