A Novel Aurora-A Inhibitor (MLN8237) Synergistically Enhances the Antitumor Activity of Sorafenib in Hepatocellular Carcinoma.
A Novel Aurora-A Inhibitor (MLN8237) Synergistically Enhances the Antitumor Activity of Sorafenib in Hepatocellular Carcinoma.
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新型 Aurora-A 抑制剂 (MLN8237) 协同增强索拉非尼在肝细胞癌中的抗肿瘤活性
DOI：
10.1016/j.omtn.2018.08.014
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发表时间：
2018-12-07
期刊：
影响因子：
--
通讯作者：
Wang R
中科院分区：
文献类型：
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作者：
Zhang K;Wang T;Zhou H;Feng B;Chen Y;Zhi Y;Wang R
目前，以索拉非尼为基础的治疗是晚期肝细胞癌（HCC）的标准治疗方法，研究其与其他药物联合使用以达到更好的治疗效果有很强的理由。Aurora-A是有丝分裂丝氨酸/苏氨酸激酶家族的成员，在人类癌症中经常过表达，因此代表了治疗的靶点。在此，我们研究了一种新的Aurora-A抑制剂MLN 8237与索拉非尼在肝癌细胞中的体外和体内作用，并阐明了可能的分子机制。研究发现，MLN 8237与索拉非尼通过改变细胞生长、细胞周期调控、细胞凋亡、迁移、侵袭和血管生成，在抑制HCC进展方面具有强烈的协同作用。机制分析表明，MLN 8237和索拉非尼联合用药可显著抑制磷酸化Akt（p-Akt）和磷酸化p38丝裂原活化蛋白激酶（p-p38 MAPK）及其下游基因（包括CDK 4、cyclinD 1和VEGFA）的活化。p-Akt和p-p38 MAPK信号传导的激活剂部分逆转了索拉非尼和MLN 8237对HCC进展的协同抑制作用。随后的体内研究进一步证实了索拉非尼和MLN 8237的协同作用。总的来说，新开发的索拉非尼-MLN 8237组合可能是一种更好地抑制HCC进展的新疗法。
Currently, sorafenib-based therapy is the standard treatment for advanced hepatocellular carcinoma (HCC), and there is a strong rationale for investigating its use in combination with other agents to achieve better therapeutic effects. Aurora-A, a member of a family of mitotic serine/threonine kinases, is frequently overexpressed in human cancers and therefore represents a target for therapy. Here, we investigated a novel Aurora-A inhibitor, MLN8237, together with sorafenib in HCC cells in vitro and in vivo, and elucidated the possible molecular mechanism. Here, it was found that MLN8237 was strongly synergistic with sorafenib in inhibition of HCC progression by altering cell growth, cell-cycle regulation, apoptosis, migration, invasion, and angiogenesis. Mechanism dissection suggests that the combination of MLN8237 and sorafenib led to significant inhibition of the activation of phospho-Akt (p-Akt) and phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) and their downstream genes including CDK4, cyclinD1, and VEGFA. The activators of p-Akt and p-p38 MAPK signaling partially reversed the synergistic inhibitory effects of sorafenib and MLN8237 on HCC progression. Subsequent in vivo studies further confirmed the synergistic effects of sorafenib and MLN8237. Collectively, the newly developed sorafenib-MLN8237 combination may be a novel therapy to better inhibit HCC progression.
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影响因子：
7.3
作者：
Birkenkamp, KU;Tuyt, LML;Vellenga, E
通讯作者：
Vellenga, E
影响因子：
45.3
作者：
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影响因子：
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作者：
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影响因子：
3.7
作者：
Dong J;Zhai B;Sun W;Hu F;Cheng H;Xu J
通讯作者：
Xu J
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影响因子：
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作者：
通讯作者：
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