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首页> 外文期刊>Gene Therapy and Molecular Biology >Gene expression signature-based chemical genomics and activity pattern in a panel of tumour cell lines propose linalyl acetate as a protein kinase/NF-κB inhibitor
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Gene expression signature-based chemical genomics and activity pattern in a panel of tumour cell lines propose linalyl acetate as a protein kinase/NF-κB inhibitor

机译：一组肿瘤细胞系中基于基因表达特征的化学基因组学和活性模式提出乙酸芳樟酯作为蛋白激酶/NF-κB抑制剂

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The essential oil of Lebanese sage, Salvia libanotica, was reported to have anti-tumour activity; however, the mechanism of action has not been identified yet. In this study, 14- cancer cell lines including drug-sensitive and resistant lung, leukaemia, and colon, as well as primary human tumours of chronic lymphocytic leukaemia (CLL) and primary normal mononuclear cells (PBMCs) were used to characterize the anti-tumour activity and mechanism of action of linalyl acetate, a component of the Lebanese sage essential oil. Drug activity and gene expression data sets were utilized to identify drugs with similar activity patterns and genes involved in drug sensitivity/resistance. In addition, the Connectivity Map, a gene expression signature-based screening approach, assisted in predicting further the molecular action of linalyl acetate. Small cell lung carcinoma and colorectal cancer cell lines were the most sensitive to the drug and greater tumour selectivity was observed against chronic lymphocytic leukaemia cells compared to normal mononuclear cells. Only limited effect of some of the classical mechanisms of multi-drug resistance on the activity of Linalyl acetate was noted which makes it potentially interesting for drug-resistant patients. There was high similarity between the activity-pattern/gene expression profile of linalyl acetate and that of protein kinase/NF-κB inhibitors. Validating this, linalyl acetate was found to strongly inhibit Janus kinase, JAK3, and p38α kinases in a cell-free assay as well as the NF-κB translocation in a dose-dependent manner. Taken together, our results show that the NF-kB inhibitor, linalyl acetate, may represent anew therapeutic compound in the management of inflammation and cancer.
机译：据报道，黎巴嫩鼠尾草的精油Salvia libanotica具有抗肿瘤活性。但是，作用机理尚未确定。在这项研究中，使用14种癌细胞系（包括药物敏感性和耐药性的肺癌，白血病和结肠癌，以及慢性淋巴细胞性白血病（CLL）的原发性人类肿瘤和原发性正常单核细胞（PBMC））来表征抗乙酸鼠尾草精油的一种成分，它具有肿瘤活性和作用机理。利用药物活性和基因表达数据集来鉴定具有相似活性模式和涉及药物敏感性/耐药性的基因的药物。此外，基于基因表达特征的筛选方法“连接图”有助于进一步预测乙酸芳樟酯的分子作用。小细胞肺癌和结肠直肠癌细胞系对该药物最敏感，与正常单核细胞相比，对慢性淋巴细胞性白血病细胞观察到更大的肿瘤选择性。仅注意到一些经典的多药耐药机制对乙酸芳樟酯活性的有限影响，这使得它对耐药患者具有潜在的意义。乙酸芳樟酯的活性模式/基因表达谱与蛋白激酶/NF-κB抑制剂的活性谱/基因表达谱高度相似。验证这一点，发现乙酸芳樟酯在无细胞测定中以剂量依赖性方式强烈抑制Janus激酶，JAK3和p38α激酶以及NF-κB易位。综上所述，我们的结果表明，NF-kB抑制剂乙酸芳基酯可能代表了一种新型的治疗炎症和癌症的治疗化合物。

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