Identification of known drugs that act as inhibitors of NF-kappaB signaling and their mechanism of action.
Identification of known drugs that act as inhibitors of NF-kappaB signaling and their mechanism of action.
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DOI：
10.1016/j.bcp.2009.12.021
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发表时间：
2010-05-01
影响因子：
5.8
通讯作者：
Xia, Menghang
中科院分区：
文献类型：
--
作者：
Miller, Susanne C.;Huang, Ruili;Sakamuru, Srilatha;Shukla, Sunita J.;Attene-Ramos, Matias S.;Shinn, Paul;Van Leer, Danielle;Leister, William;Austin, Christopher P.;Xia, Menghang
关键词：
核因子-κ B（NF-κB）是一种转录因子，在胚胎和神经元发育、细胞增殖、细胞凋亡、感染免疫应答和炎症等许多细胞过程中发挥关键作用。NF-κB信号转导的失调与炎性疾病和某些癌症相关。NF-κB信号通路在乳腺癌、结肠癌、前列腺癌、皮肤癌和淋巴癌等多种肿瘤中存在组成性激活，因此阻断肿瘤细胞中NF-κB信号通路为开发抗肿瘤药物提供了一个有吸引力的策略。为了鉴定NF-κB信号传导的小分子抑制剂，我们在NF-κB介导的β-内酰胺酶报告基因试验中从NIH化学基因组学中心药物保藏中心（NPC）筛选了约2，800种临床批准的药物和生物活性化合物。以定量高通量筛选形式在15种不同浓度下测试每种化合物。我们鉴定了19种抑制NF-κB信号传导的药物，效力低至20 nM。这些药物中的许多药物，包括恩替卡韦、氟柳胺、苹果酸舒尼替尼、双硫昂诺、甲基盐霉素、三溴柳胺和来替尼，通过抑制IκBα磷酸化来抑制NF-κB信号传导。其他的，如海鞘素743，色霉素A3和硼替佐米利用其他机制。此外，这些药物中的许多诱导caspase 3/7活性，并对宫颈癌细胞生长具有抑制作用。我们的研究结果表明，许多目前批准的药物对NF-κB信号传导具有以前未被认识到的作用，这可能有助于抗癌治疗效果。对已批准药物的全面分析可以深入了解其分子机制，从而为药物再利用提供基础。
Nuclear factor-kappa B (NF-κB) is a transcription factor that plays a critical role across many cellular processes including embryonic and neuronal development, cell proliferation, apoptosis, immune responses to infection, and inflammation. Dysregulation of NF-κB signaling is associated with inflammatory diseases and certain cancers. Constitutive activation of NF-κB signaling has been found in some types of tumors including breast, colon, prostate, skin and lymphoid, hence therapeutic blockade of NF-κB signaling in cancer cells provides an attractive strategy for the development of anticancer drugs. To identify small molecule inhibitors of NF-κB signaling, we screened approximately 2,800 clinically approved drugs and bioactive compounds from the NIH Chemical Genomics Center Pharmaceutical Collection (NPC) in a NF-κB mediated β-lactamase reporter gene assay. Each compound was tested at fifteen different concentrations in a quantitative high throughput screening format. We identified nineteen drugs that inhibited NF-κB signaling, with potencies as low as 20 nM. Many of these drugs, including emetine, fluorosalan, sunitinib malate, bithionol, narasin, tribromsalan, and lestaurtinib, inhibited NF-κB signaling via inhibition of IκBα phosphorylation. Others, such as ectinascidin 743, chromomycin A3 and bortezomib utilized other mechanisms. Furthermore, many of these drugs induced caspase 3/7 activity and had an inhibitory effect on cervical cancer cell growth. Our results indicate that many currently approved pharmaceuticals have previously unappreciated effects on NF-κB signaling, which may contribute to anticancer therapeutic effects. Comprehensive profiling of approved drugs provides insight into their molecular mechanisms, thus providing a basis for drug repurposing.
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影响因子：
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作者：
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通讯作者：
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DOI：
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