Zou Hui, Cao Xiaozheng, Xiao Qiao, Sheng Xifeng, Ren Kaiqun, Quan Meifang, Song Zhengwei, Li Duo, Zheng Yu, Zeng Wenbin, Cao Jianguo, Peng Yaojin
Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
School of Pharmaceutical Sciences, and Molecular Imaging Research Center, Central South University, Changsha, Hunan 410013, P.R. China.
Oncol Rep. 2016 Sep;36(3):1731-8. doi: 10.3892/or.2016.4973. Epub 2016 Jul 25.
Sorafenib, a multi-kinase inhibitor, has shown its promising antitumor effect in a series of clinical trials, and has been approved as the current standard treatment for advanced hepatocellular carcinoma (HCC). 8-Bromo‑7-methoxychrysin (BrMC) is a novel chrysin synthetic analogue that has been reported to inhibit the growth of various tumor cells and possess properties for targeting liver cancer stem cells (LCSCs) . The present study investigated the synergistic targeting effects on the properties of liver cancer stem-like cells (LCSLCs) by a combination of sorafenib and BrMC in SMMC-7721 cell line. We also investigated whether this effect involves regulation of HIF-1α, Twist and NF-κB protein. We found that the sphere-forming cells (SFCs) from the SMMC‑7721 cells possessed the properties of LCSLCs. Sorafenib diminished the self-renewal capacity and downregulated the expression of stem cell biomarkers (CD133, CD44 and ALDH1) in a dose-dependent manner, while BrMC cooperated with sorafenib to strengthen this inhibition. Moreover, the combination of sorafenib and BrMC led to a remarkable decrease in the cellular migration and invasion, the downregulation of N-cadherin protein and upregulation of E-cadherin protein, and increase of cell apoptosis in LCSLCs. BrMC has a remarkable antagonistic effect on the upregulation of protein expression and DNA binding activity of NF-κB (p65) induced by sorafenib. In addition, our results indicated that the synergistic inhibition of sorafenib and BrMC on the characteristics of LCSLCs involves the downregulated expression of HIF-1α and EMT regulator Twist1. Collectively, the combination therapy of sorafenib and BrMC could be a new and promising therapeutic approach in the treatment of HCC.
索拉非尼是一种多激酶抑制剂，在一系列临床试验中已显示出其有前景的抗肿瘤作用，并已被批准作为晚期肝细胞癌（HCC）的当前标准治疗方法。8-溴-7-甲氧基白杨素（BrMC）是一种新型的白杨素合成类似物，据报道它能抑制各种肿瘤细胞的生长，并具有靶向肝癌干细胞（LCSCs）的特性。本研究调查了索拉非尼和BrMC联合对SMMC-7721细胞系中肝癌干细胞样细胞（LCSLCs）特性的协同靶向作用。我们还研究了这种作用是否涉及对HIF-1α、Twist和NF-κB蛋白的调节。我们发现SMMC-7721细胞的成球细胞（SFCs）具有LCSLCs的特性。索拉非尼以剂量依赖性方式降低了自我更新能力并下调了干细胞生物标志物（CD133、CD44和ALDH1）的表达，而BrMC与索拉非尼协同增强了这种抑制作用。此外，索拉非尼和BrMC的联合导致LCSLCs的细胞迁移和侵袭显著减少，N-钙黏蛋白蛋白下调，E-钙黏蛋白蛋白上调，以及细胞凋亡增加。BrMC对索拉非尼诱导的NF-κB（p65）蛋白表达上调和DNA结合活性具有显著的拮抗作用。此外，我们的结果表明，索拉非尼和BrMC对LCSLCs特性的协同抑制涉及HIF-1α和EMT调节因子Twist1的表达下调。总体而言，索拉非尼和BrMC的联合治疗可能是治疗HCC的一种新的且有前景的治疗方法。
