Inhibition of Hec1 as a novel approach for treatment of primary liver cancer
Inhibition of Hec1 as a novel approach for treatment of primary liver cancer
复制标题
DOI：
10.1007/s00280-014-2540-7
复制
发表时间：
2014-09-01
影响因子：
3
通讯作者：
Lau, Johnson Y. N.
中科院分区：
文献类型：
--
作者：
Huang, Lynn Y. L.;Chang, Chia-chi;Lau, Johnson Y. N.
癌高表达蛋白1(Hec1)是一种癌基因，有望成为新型抗癌药物的分子靶点。本研究的目的是评估Hec1抑制剂TAI-95用于治疗原发性肝癌的可能性，并采用体内外方法检测其活性。体外生长抑制结果显示，TAI-95对多种原发肝癌细胞株(肝母细胞瘤或肝细胞癌)(GI(50)30-70 nm)具有良好的抑制作用，优于索拉非尼和其他细胞毒药物。TAI-95在非癌细胞系(GI(50)和GT；10亩M)中活性相对较低。TAI-95干扰Hec1和Nek2之间的相互作用，导致Nek2降解、染色体错位和细胞凋亡。TAI-95与阿霉素、紫杉醇、拓扑替康有协同作用，但与索拉非尼无协同作用。TAI-95在HUH-7异种移植小鼠模型中口服时显示出极好的效力。临床标本的基因表达分析显示，27%的患者Hec1/NDC80及其相关基因(Nek2、SMC1A和SMC2)的表达增加，这突显了这种治疗方法用于靶向Hec1高表达患者的潜力。用小分子方法抑制Hec1可能是治疗原发性肝癌的一种有前途的新方法。
Highly expressed in cancer protein 1 (Hec1) is an oncogene and a promising molecular target for novel anticancer drugs. The purpose of this study was to evaluate the potential of a Hec1 inhibitor, TAI-95, as a treatment for primary liver cancer.In vitro and in vivo methods were used to test the activity of TAI-95. Gene expression analysis was used to evaluate clinical correlation of the target.In vitro growth inhibition results showed that TAI-95 has excellent potency on a wide range of primary liver cancer cell lines (hepatoblastoma or hepatocellular carcinoma) (GI(50) 30-70 nM), which was superior to sorafenib and other cytotoxic agents. TAI-95 was relatively inactive in non-cancerous cell lines (GI(50) > 10 mu M). TAI-95 disrupts the interaction between Hec1 and Nek2 and leads to degradation of Nek2, chromosomal misalignment, and apoptotic cell death. TAI-95 showed synergistic activity in selected cancer cell lines with doxorubicin, paclitaxel, and topotecan, but not with sorafenib. TAI-95 shows excellent potency in a Huh-7 xenograft mouse model when administered orally. Gene expression analysis of clinical samples demonstrated increased expression of Hec1/NDC80 and associated genes (Nek2, SMC1A, and SMC2) in 27 % of patients, highlighting the potential for using this therapeutic approach to target patients with high Hec1 expression.Inhibition of Hec1 using small molecule approach may represent a promising novel approach for the treatment of primary liver cancers.