Cytotoxic activity of the novel small molecule AKT inhibitor SC66 in hepatocellular carcinoma cells.
Cytotoxic activity of the novel small molecule AKT inhibitor SC66 in hepatocellular carcinoma cells.
复制标题
DOI：
10.18632/oncotarget.2738
复制
发表时间：
2015-01-30
期刊：
影响因子：
--
通讯作者：
Cervello M
中科院分区：
文献类型：
--
作者：
Cusimano A;Puleio R;D'Alessandro N;Loria GR;McCubrey JA;Montalto G;Cervello M
肝细胞癌（HCC）的特点是对目前的药物治疗反应有限。在这里，我们报告，SC 66，一种新的AKT抑制剂，降低细胞活力的剂量和时间依赖性的方式，抑制集落形成和诱导肝癌细胞凋亡。SC 66处理导致总AKT水平和磷酸化AKT水平降低。这与细胞骨架组织的改变、E-钙粘蛋白、β-连环蛋白和磷酸化FAK表达水平的降低以及Snail蛋白水平的上调有关。所有这些改变都伴随着失巢凋亡细胞死亡诱导。此外，SC 66诱导活性氧（ROS）的产生和DNA损伤。用ROS清除剂N-乙酰半胱氨酸（NAC）预处理可防止SC 66诱导的细胞生长抑制和失巢凋亡。SC 66分别显著增强了常规化疗剂和靶向药物多柔比星和依维莫司的作用。在体内，SC 66抑制异种移植模型中Hep 3B细胞的肿瘤生长，在体外模型中观察到类似的机制。综上所述，这些数据表明AKT抑制剂SC 66对HCC细胞具有抗肿瘤作用。这是由ROS的产生，诱导失巢凋亡介导的细胞死亡和抑制AKT细胞存活途径介导的。本研究结果为SC 66在肝癌治疗中的应用提供了依据。
Hepatocellular carcinoma (HCC) is characterized by limited response to current drug therapies. Here, we report that SC66, a novel AKT inhibitor, reduced cell viability in a dose- and time-dependent manner, inhibited colony formation and induced apoptosis in HCC cells. SC66 treatment led to a reduction in total and phospho-AKT levels. This was associated with alterations in cytoskeleton organization, a reduction in expression levels of E-cadherin, β-catenin and phospho-FAK, together with up-regulation of Snail protein levels. All these alterations were coupled with anoikis cell death induction. In addition, SC66 induced the production of reactive oxygen species (ROS) and DNA damage. Pre-treatment with the ROS scavenger N-Acetyl-cysteine (NAC) prevented SC66-induced cell growth inhibition and anoikis. SC66 significantly potentiated the effects of both conventional chemotherapeutic and targeted agents, doxorubicin and everolimus, respectively. In vivo, SC66 inhibited tumor growth of Hep3B cells in xenograft models, with a similar mechanism observed in the in vitro model. Taken together, these data indicate that the AKT inhibitor SC66 had antitumor effects on HCC cells. This was mediated by ROS production, induction of anoikis-mediated cell death and inhibition of the AKT cell survival pathway. Our results provide a rational basis for the use of SC66 in HCC treatment.
登录
查看更多内容
影响因子：
29.4
作者：
El-Serag HB
通讯作者：
El-Serag HB
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
DOI：
10.1073/pnas.1019062108
发表时间：
2011-04-19
影响因子：
11.1
作者：
Jo, Hakryul;Lo, Pang-Kuo;Luo, Hongbo R.
通讯作者：
Luo, Hongbo R.
影响因子：
45.3
作者：
Abou-Alfa, Ghassan K.;Schwartz, Lawrence;Saltz, Leonard B.
通讯作者：
Saltz, Leonard B.
影响因子：
4.5
作者：
Peyre, Ludovic;Zucchini-Pascal, Nathalie;Rahmani, Roger
通讯作者：
Rahmani, Roger