靶向 RAS/RAF/MAPK 和 WNT/β-catenin 通路协同抑制 HCC 和肝癌干细胞增殖。
Synergistic inhibition of HCC and liver cancer stem cell proliferation by targeting RAS/RAF/MAPK and WNT/β-catenin pathways.
机构信息
800 Rose Street, Room C453, Lexington, Kentucky 40536-0293, U.S.A.
出版信息
Anticancer Res. 2014 Apr;34(4):1709-13.
BACKGROUND/AIM: The aim of this study is to find synergistic effect using FH535 and sorafenib by targeting the RAS/RAF/MAPK and WNT/β-catenin pathways.
MATERIALS AND METHODS
3H-Thymidine incorporation assays were performed to address Huh7 and liver cancer stem cell (LCSC) inhibition using FH535 and sorafenib, alone and in combination. Calcusyn analysis was used to calculate the combination index (CI). A western blot assay was performed to check for potential targets.
RESULTS
FH535 and sorafenib caused inhibition of Huh7 and LCSC. Combination therapy was significantly better than monotherapy in inhibition of HuH7. Combination with sorafenib and FH535 was found to be synergistic in inhibition of LCSC with a CI of less than 1. The western blot assay demonstrated enhanced cleaved poly (ADP-ribose) polymerase (PARP) and inhibition of cyclin D1, B-cell lymphoma 2 (Bcl2), survivin and cellular myelocytomatosis oncogene (c-MYC).
CONCLUSION
FH535 and sorafenib combination produced synergistic effect on inhibition of HCC and LCSC. Our study demonstrated that FH535 can induce apoptosis in these two different hepatocellular carcinoma (HCC) cell lines.
背景/目的：本研究旨在通过靶向 RAS/RAF/MAPK 和 WNT/β-连环蛋白通路，寻找 FH535 和索拉非尼联合使用的协同效应。
材料和方法
采用 3H-胸腺嘧啶掺入试验，单独及联合使用 FH535 和索拉非尼，检测对 Huh7 和肝癌干细胞（LCSC）的抑制作用。Calcusyn 分析用于计算联合指数（CI）。采用 Western blot 检测潜在靶点。
结果
FH535 和索拉非尼均可抑制 Huh7 和 LCSC。联合治疗对 HuH7 的抑制作用明显优于单药治疗。联合应用索拉非尼和 FH535 对 LCSC 的抑制作用呈协同作用，CI 值小于 1。Western blot 检测显示，FH535 和索拉非尼联合应用可增强裂解多聚（ADP-核糖）聚合酶（PARP），抑制细胞周期蛋白 D1、B 细胞淋巴瘤 2（Bcl2）、存活素和髓细胞细胞瘤癌基因（c-MYC）。
结论
FH535 和索拉非尼联合应用对 HCC 和 LCSC 的抑制具有协同作用。我们的研究表明，FH535 可以诱导这两种不同的肝癌细胞系发生凋亡。
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