CG200745, an HDAC inhibitor, induces anti-tumour effects in cholangiocarcinoma cell lines via miRNAs targeting the Hippo pathway.
CG200745, an HDAC inhibitor, induces anti-tumour effects in cholangiocarcinoma cell lines via miRNAs targeting the Hippo pathway.
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DOI：
10.1038/s41598-017-11094-3
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发表时间：
2017-09-07
影响因子：
4.6
通讯作者：
Song SY
中科院分区：
文献类型：
--
作者：
Jung DE;Park SB;Kim K;Kim C;Song SY
胆管癌是一种具有致命并发症的毁灭性恶性肿瘤，对化疗反应低且耐药。在这里，我们评估了CG 200745，一种新的组蛋白去乙酰化酶抑制剂，单独使用或与标准化疗药物联合使用对胆管癌细胞的抗癌作用。CG 200745剂量依赖性地降低体外胆管癌细胞的活力，并降低异种移植模型中的肿瘤体积和重量。将CG 200745沿着与其他化疗剂（包括吉西他滨、5-氟尿嘧啶（5-FU）、顺铂、奥沙利铂或吉西他滨加顺铂）一起施用进一步降低胆管癌细胞活力，其中组合指数< 1，表明协同作用。CG 200745还增强了吉西他滨耐药细胞对吉西他滨和5-FU的敏感性，从而降低细胞活力并诱导细胞凋亡。这伴随着雅普、TEAD 4、TGF-β2、SMAD 3、N 0 TCH 3、HES 5、Axl和Gas 6的下调以及miR-22- 3 p、miR-22- 5 p、miR-194- 5 p、miR-194- 3 p、miR-194 - 5 p、miR-210- 3 p和miR-509- 3 p的上调。免疫途径分析显示，CG 200745主要通过诱导miR-509- 3 p表达靶向Hippo信号通路。因此，CG 200745在体外和体内抑制胆管癌生长，并且当与标准化疗剂组合施用时协同作用，使得能够降低剂量。因此，CG 200745有望改善对常规疗法表现出耐药性的胆管癌患者的结局。
Cholangiocarcinoma is a devastating malignancy with fatal complications that exhibits low response and resistance to chemotherapy. Here, we evaluated the anticancer effects of CG200745, a novel histone deacetylase inhibitor, either alone or in combination with standard chemotherapy drugs in cholangiocarcinoma cells. CG200745 dose-dependently reduced the viability of cholangiocarcinoma cells in vitro and decreased tumour volume and weight in a xenograft model. Administering CG200745 along with other chemotherapeutic agents including gemcitabine, 5-fluorouracil (5-FU), cisplatin, oxaliplatin, or gemcitabine plus cisplatin further decreased cholangiocarcinoma cell viability, with a combination index < 1 that indicated synergistic action. CG200745 also enhanced the sensitivity of gemcitabine-resistant cells to gemcitabine and 5-FU, thereby decreasing cell viability and inducing apoptosis. This was accompanied by downregulation of YAP, TEAD4, TGF-β2, SMAD3, NOTCH3, HES5, Axl, and Gas6 and upregulation of the miRNAs miR-22-3p, miR-22-5p, miR-194-5p, miR-194-3p, miR-194-5p, miR-210-3p, and miR-509-3p. The Ingenuity Pathway Analysis revealed that CG200745 mainly targets the Hippo signalling pathway by inducing miR-509-3p expression. Thus, CG200745 inhibits cholangiocarcinoma growth in vitro and in vivo, and acts synergistically when administered in combination with standard chemotherapeutic agents, enabling dose reduction. CG200745 is therefore expected to improve the outcome of cholangiocarcinoma patients who exhibit resistance to conventional therapies.
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DOI：
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期刊：
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