Targeting the IL-6 dependent phenotype can identify novel therapies for cholangiocarcinoma.
Targeting the IL-6 dependent phenotype can identify novel therapies for cholangiocarcinoma.
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DOI：
10.1371/journal.pone.0015195
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发表时间：
2010-12-16
期刊：
影响因子：
3.7
通讯作者：
Patel T
中科院分区：
文献类型：
--
作者：
Braconi C;Swenson E;Kogure T;Huang N;Patel T
胆管癌的预后差和化疗难治性突出了对新疗法的需求。白细胞介素-6的产生增加促进胆管癌的生长，并通过激活细胞存活机制而导致化疗耐药性。我们试图鉴定能够改善IL-6表达的表型效应的生物活性化合物，并探索其对胆管癌的潜在治疗用途。推导出与Mz-ChA-1人恶性胆管细胞中白细胞介素-6表达相关的基因组签名。进行计算生物信息学分析以鉴定诱导标签的逆基因变化的化合物。这些化合物对胆管癌生长的影响，然后在体外和体内实验验证。使用中位效应分析评价与其他治疗药物的相互作用。一组结构相关的化合物，尼群地平，硝苯地平和非洛地平被确定。所有三种化合物对Mz-ChA-1细胞都具有细胞毒性，非洛地平的IC 50为26 μM，尼群地平为44 μM，硝苯地平为15 μM。在KMCH-1、CC-LP-1和TFK-1胆管癌细胞系中观察到类似的结果。在分数效应为0.5时，所有三种药物与喜树碱或吉西他滨在体外Mz-ChA-1细胞中具有协同作用。非洛地平和吉西他滨联合给药可降低裸鼠Mz-ChA-1细胞移植瘤的生长。基于表型的基因组表达的计算生物信息学分析可用于鉴定治疗剂。使用这种基于靶向确定的肿瘤相关表型的药物发现方法，我们鉴定了具有治疗胆管癌潜力的化合物。
The need for new therapies for cholangiocarcinoma is highlighted by their poor prognosis and refractoriness to chemotherapy. Increased production of Interleukin-6 promotes cholangiocarcinoma growth and contributes to chemoresistance by activating cell survival mechanisms. We sought to identify biologically active compounds capable of ameliorating the phenotypic effects of IL-6 expression and to explore their potential therapeutic use for cholangiocarcinoma. A genomic signature associated with Interleukin-6 expression in Mz-ChA-1 human malignant cholangiocytes was derived. Computational bioinformatics analysis was performed to identify compounds that induced inverse gene changes to the signature. The effect of these compounds on cholangiocarcinoma growth was then experimentally verified in vitro and in vivo. Interactions with other therapeutic agents were evaluated using median effects analysis. A group of structurally related compounds, nitrendipine, nifedipine and felodipine was identified. All three compounds were cytotoxic to Mz-ChA-1 cells with an IC50 for felodipine of 26 µM, nitrendipine, 44 µM and nifedipine, 15 µM. Similar results were observed in KMCH-1, CC-LP-1 and TFK-1 cholangiocarcinoma cell lines. At a fractional effect of 0.5, all three agents were synergistic with either camptothecin or gemcitabine in Mz-ChA-1 cells in vitro. Co-administration of felodipine and gemcitabine decreased the growth of Mz-ChA-1 cell xenografts in nude athymic mice. Computational bioinformatics analysis of phenotype-based genomic expression can be used to identify therapeutic agents. Using this drug discovery approach based on targeting a defined tumor associated phenotype, we identified compounds with the potential for therapeutic use in cholangiocarcinoma.
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