Antitumor activity of TY-011 against gastric cancer by inhibiting Aurora A, Aurora B and VEGFR2 kinases.
Antitumor activity of TY-011 against gastric cancer by inhibiting Aurora A, Aurora B and VEGFR2 kinases.
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TY-011 通过抑制 Aurora A、Aurora B 和 VEGFR2 激酶发挥抗胃癌活性。
DOI：
10.1186/s13046-016-0464-2
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发表时间：
2016-11-25
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Liu W;Lu Y;Chai X;Liu X;Zhu T;Wu X;Fang Y;Liu X;Zhang X
Aurora A和B的过表达在包括胃癌在内的多种肿瘤类型中都有报道。抗血管生成已被认为是晚期胃癌的一种重要治疗方式。在这里，我们发现了一种新的化合物TY-011，它通过靶向有丝分裂激酶（Aurora a和B）和血管生成受体酪氨酸激酶（VEGFR2）具有很好的抗肿瘤活性。采用HTRF®KinEASE™检测TY-011对Aurora A、Aurora B和VEGFR2活性的影响。对接模拟研究预测TY-011与Aurora A和B激酶的结合模式。CCK-8法检测细胞生长情况。流式细胞术分析细胞周期和细胞凋亡。采用胃癌细胞异种移植小鼠模型进行体内研究。TUNEL试剂盒检测肿瘤组织的凋亡情况。采用免疫组化分析和HUVEC成管实验检测其抗血管生成能力。免疫荧光和western blot检测蛋白表达。通过HTRF®KinEASE™检测，TY-011被鉴定为潜在的Aurora a和B抑制剂。有效抑制细胞极光A和极光B的活性，并呈浓度依赖性。TY-011占据了Aurora A和B激酶的atp结合位点。TY-011对胃癌细胞的增殖有明显的抑制作用。TY-011处理诱导G2/M期细胞明显聚集，bbb40n DNA含量适度增加，随后发生凋亡。有意义的是，口服TY-011对异种胃癌细胞的肿瘤生长具有优越的抑制作用，在9 mg/kg的剂量下，抑制率约为90%，肿瘤消退100%，并且TY-011对小鼠的体重没有影响。有趣的是，我们观察到TY-011也通过靶向VEGFR2激酶拮抗肿瘤血管生成。这些结果表明，TY-011是一种耐受性良好的口服活性化合物，可靶向肿瘤生长中的有丝分裂和血管生成，为治疗人类胃癌提供了强有力的临床前支持。本文的在线版本（doi:10.1186/s13046-016-0464-2）包含补充材料，可供授权用户使用。
Overexpression of Aurora A and B has been reported in a wide range of tumor types, including gastric cancer. Anti-angiogenesis has been considered as an important therapeutic modality in advanced gastric cancer. Here we identified a novel compound TY-011 with promising antitumor activity by targeting mitotic kinases (Aurora A and B) and angiogenic receptor tyrosine kinase (VEGFR2). HTRF® KinEASE™ assay was used to detect the effect of TY-011 against Aurora A, Aurora B and VEGFR2 activities. Docking simulation study was performed to predict the binding mode of TY-011 with Aurora A and B kinases. CCK-8 assay was used to test cell growth. Cell cycle and cell apoptosis was analyzed by flow cytometry. Gastric cancer cell xenograft mouse models were used for in vivo study. TUNEL kit was used to determine the apoptosis of tumor tissues. Immunohistochemistry analysis and HUVEC tube formation assay were performed to determine the anti-angiogenesis ability. Immunofluorescence and western blot were used to test protein expression. TY-011 was identified as a potential Aurora A and B inhibitor by HTRF® KinEASE™ assay. It effectively inhibited cellular Aurora A and B activities in a concentration-dependent manner. TY-011 occupied the ATP-binding site of both Aurora A and B kinases. TY-011 demonstrated prominent inhibitory effects on proliferation of gastric cancer cells. TY-011 treatment induced an obvious accumulation of cells at G2/M phase and a modest increase of cells with >4 N DNA content, which then underwent apoptosis. Meaningfully, orally administration of TY-011 demonstrated superior efficacy against the tumor growth in gastric cancer cell xenograft, with ~90% inhibition rate and 100% tumor regression at 9 mg/kg dose, and TY-011 did not affect the body weight of mice. Interestingly, we observed that TY-011 also antagonized tumor angiogenesis by targeting VEGFR2 kinase. These results indicate that TY-011 is a well-tolerated, orally active compound that targets mitosis and angiogenesis in tumor growth, and provides strong preclinical support for use as a therapeutic for human gastric cancers. The online version of this article (doi:10.1186/s13046-016-0464-2) contains supplementary material, which is available to authorized users.
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影响因子：
4.7
作者：
Reboutier D;Benaud C;Prigent C
通讯作者：
Prigent C
影响因子：
2.7
作者：
Curtin, Michael L.;Frey, Robin R.;Michaelides, Michael R.
通讯作者：
Michaelides, Michael R.
DOI：
10.1186/s13046-016-0310-6
发表时间：
2016-02-24
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Dorward HS;Du A;Bruhn MA;Wrin J;Pei JV;Evdokiou A;Price TJ;Yool AJ;Hardingham JE
通讯作者：
Hardingham JE
影响因子：
5.7
作者：
Fletcher, Graham C.;Brokx, Richard D.;Bray, Mark R.
通讯作者：
Bray, Mark R.
影响因子：
--
作者：
Arjaans M;Schröder CP;Oosting SF;Dafni U;Kleibeuker JE;de Vries EG
通讯作者：
de Vries EG