Aurora Kinase Inhibitor PHA-739358 Suppresses Growth of Hepatocellular Carcinoma In Vitro and in a Xenograft Mouse Model
Aurora Kinase Inhibitor PHA-739358 Suppresses Growth of Hepatocellular Carcinoma In Vitro and in a Xenograft Mouse Model
复制标题
DOI：
10.1593/neo.09664
复制
发表时间：
2009-09-01
期刊：
影响因子：
4.8
通讯作者：
Brummendorf, Tim H.
中科院分区：
文献类型：
--
作者：
Benten, Daniel;Keller, Gunhild;Brummendorf, Tim H.
晚期肝细胞癌患者预后较差。尽管多激酶抑制剂索拉非尼已经取得了令人鼓舞的临床结果，但发展更好的肝癌治疗策略仍然是一个紧迫的目标。极光激酶是细胞周期的关键调节因子，它们的不受控制的表达促进了非整倍体和肿瘤的发展。在组织芯片分析中，我们检测到所有93例人肝细胞癌标本中AURORA-A蛋白的表达，而AURORA-B蛋白的表达水平与肝癌细胞的增殖指数显著相关。此外，两个人肝癌细胞系(Huh-7和HepG2)的AURORA-A和-B检测呈阳性，并显示组蛋白H3的Ser10磷酸化，表明OURORA-B激酶活性增加。一种新的极光激酶抑制剂，PHA-739358，目前正在其他实体肿瘤的第二阶段临床试验中进行研究，在体外和体内进行了抗增殖特性的检测。在细胞培养实验中，当浓度超过50 nm时，PHA-739358完全抑制肿瘤细胞的增殖，并显著降低组蛋白H3的磷酸化。在50 nM时，细胞周期受到抑制和内复制，而较高浓度则导致细胞完全停滞在G(2)/M期。在体内，在耐受性良好的剂量下，给予PHA-739358可显著抑制肿瘤生长。与索拉非尼联合应用时，可观察到相加效应。值得注意的是，当肿瘤在索拉非尼单一治疗下重新开始生长时，随后使用PHA-739358的治疗导致肿瘤缩小高达81%。因此，用PHA-739358靶向极光激酶是一种对晚期肝癌患者单独或与索拉非尼联合应用的有前景的治疗策略。
Patients with advanced stages of hepatocellular carcinoma (HCC) face a poor prognosis. Although encouraging clinical results have been obtained with multikinase inhibitor sorafenib, the development of improved therapeutic strategies for HCC remains an urgent goal. Aurora kinases are key regulators of the cell cycle, and their uncontrolled expression promotes aneuploidy and tumor development. In tissue microarray analyses, we detected aurora-A kinase expression in all of the examined 93 human HCC samples, whereas aurora-B kinase expression levels significantly correlated with the proliferation index of HCCs. In addition, two human HCC cell lines (Huh-7 and HepG2) were tested positive for aurora-A and -B and revealed Ser10 phosphorylation of histone H3, indicating an increased aurora-B kinase activity. The antiproliferative features of a novel aurora kinase inhibitor, PHA-739358, currently under investigation in phase 2 clinical trials for other solid tumors, were examined in vitro and in vivo. At concentrations exceeding 50nM, PHA-739358 completely suppressed tumor cell proliferation in cell culture experiments and strongly decreased histone H3 phosphorylation. Cell cycle inhibition and endoreduplication were observed at 50 nM, whereas higher concentrations led to a complete G(2)/M-phase arrest. In vivo, administration of PHA-739358 resulted in significant tumor growth inhibition at a well-tolerated dose. In combination with sorafenib, additive effects were observed. Remarkably, when tumors restarted to grow under sorafenib monotherapy, subsequent treatment with PHA-739358 induced tumor shrinkage by up to 81%. Thus, targeting aurora kinases with PHA-739358 is a promising therapeutic strategy administered alone or in combination with sorafenib for patients with advanced stages of HCC.