Chen Chun-Han, Chen Mei-Chuan, Wang Jing-Chi, Tsai An-Chi, Chen Ching-Shih, Liou Jing-Ping, Pan Shiow-Lin, Teng Che-Ming
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
The Ph.D. program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Clin Cancer Res. 2014 Mar 1;20(5):1274-1287. doi: 10.1158/1078-0432.CCR-12-3909. Epub 2014 Feb 11.
To investigate the antitumor activities of a histone deacetylase (HDAC) inhibitor, MPT0E028, plus sorafenib in liver cancer cells in vitro and in vivo.
Different liver cancer cell lines were exposed to sorafenib in the presence or absence of MPT0E028, and cell viability was determined by MTT assay. Effects of combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and Western blot analysis. The Hep3B xenograft model was used to examine the antitumor activity in vivo.
Our data indicate that sorafenib and MPT0E028 synergistically reduced cell viability in liver cancer cells, and also markedly induced apoptotic cell death in these cells, as evidenced by the cleavage of caspase-3, PARP, and DNA fragmentation. MPT0E028 altered the global modifications of histone and nonhistone proteins regardless of the presence of sorafenib. However, sorafenib blocked MPT0E028-induced Erk activation and its downstream signaling cascades, such as Stat3 phosphorylation (Ser(727)) and Mcl-1 upregulation. Ectopic expression of constitutively active Mek successively reversed the apoptosis triggered by the combined treatment. Pharmacologic inhibition of Mek by PD98059 potentiated MPT0E028-induced apoptosis, suggesting that the synergistic interaction between MPT0E028 and sorafenib occurs at least partly through inhibition of Erk signaling. The data demonstrated that transcriptional activation of fibroblast growth factor receptor 3 (FGFR3) contributes to MPT0E028-mediated Erk phosphorylation. Finally, MPT0E028 plus sorafenib significantly improved the tumor growth delay (TGD) in a Hep3B xenograft model.
These findings suggest that MPT0E028 in combination with sorafenib has significant anti-hepatocellular carcinoma activity in preclinical models, potentially suggesting a novel therapeutic strategy for patients with advanced hepatocellular carcinoma.
研究组蛋白去乙酰化酶（HDAC）抑制剂MPT0E028联合索拉非尼在体外和体内肝癌细胞中的抗肿瘤活性。
将不同的肝癌细胞系在有或无MPT0E028的情况下暴露于索拉非尼，通过MTT法测定细胞活力。通过流式细胞术和蛋白质印迹分析评估联合治疗对细胞周期和细胞内信号通路的影响。使用Hep3B异种移植模型在体内检测抗肿瘤活性。
我们的数据表明，索拉非尼和MPT0E028协同降低肝癌细胞的活力，并显著诱导这些细胞发生凋亡性细胞死亡，这通过半胱天冬酶-3、聚（ADP-核糖）聚合酶的裂解和DNA片段化得以证明。无论有无索拉非尼，MPT0E028都会改变组蛋白和非组蛋白的整体修饰。然而，索拉非尼阻断了MPT0E028诱导的Erk激活及其下游信号级联反应，如Stat3磷酸化（Ser(727)）和Mcl-1上调。组成型活性Mek的异位表达相继逆转了联合治疗引发的凋亡。PD98059对Mek的药理学抑制增强了MPT0E028诱导的凋亡，表明MPT0E028和索拉非尼之间的协同相互作用至少部分是通过抑制Erk信号传导发生的。数据表明，成纤维细胞生长因子受体3（FGFR3）的转录激活有助于MPT0E028介导的Erk磷酸化。最后，MPT0E028联合索拉非尼显著改善了Hep3B异种移植模型中的肿瘤生长延迟（TGD）。
这些发现表明，MPT0E028联合索拉非尼在临床前模型中具有显著的抗肝细胞癌活性，这可能为晚期肝细胞癌患者提供一种新的治疗策略。
