NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Biochem Pharmacol. 2010 May 1;79(9):1272-80. doi: 10.1016/j.bcp.2009.12.021. Epub 2010 Jan 11.
Nuclear factor-kappa B (NF-kappaB) is a transcription factor that plays a critical role across many cellular processes including embryonic and neuronal development, cell proliferation, apoptosis, and immune responses to infection and inflammation. Dysregulation of NF-kappaB signaling is associated with inflammatory diseases and certain cancers. Constitutive activation of NF-kappaB signaling has been found in some types of tumors including breast, colon, prostate, skin and lymphoid, hence therapeutic blockade of NF-kappaB signaling in cancer cells provides an attractive strategy for the development of anticancer drugs. To identify small molecule inhibitors of NF-kappaB signaling, we screened approximately 2800 clinically approved drugs and bioactive compounds from the NIH Chemical Genomics Center Pharmaceutical Collection (NPC) in a NF-kappaB mediated beta-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-kappaB signaling, with potencies as low as 20 nM. Many of these drugs, including emetine, fluorosalan, sunitinib malate, bithionol, narasin, tribromsalan, and lestaurtinib, inhibited NF-kappaB signaling via inhibition of IkappaBalpha 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-kappaB 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.
核因子-κB（NF-κB）是一种转录因子，在许多细胞过程中发挥着关键作用，包括胚胎和神经元发育、细胞增殖、凋亡以及对感染和炎症的免疫反应。NF-κB 信号转导的失调与炎症性疾病和某些癌症有关。在某些类型的肿瘤中发现 NF-κB 信号的组成性激活，包括乳腺癌、结肠癌、前列腺癌、皮肤癌和淋巴样癌，因此在癌细胞中阻断 NF-κB 信号转导为开发抗癌药物提供了一个有吸引力的策略。为了鉴定 NF-κB 信号转导的小分子抑制剂，我们在 NF-κB 介导的β-内酰胺酶报告基因测定中筛选了大约 2800 种来自 NIH 化学基因组学中心药物收藏（NPC）的临床批准药物和生物活性化合物。每种化合物在定量高通量筛选格式中以十五种不同浓度进行测试。我们鉴定了十九种抑制 NF-κB 信号转导的药物，其效力低至 20 nM。这些药物中的许多，包括依米丁、氟烷、舒尼替尼马来酸盐、双硫仑、那拉菌素、三溴沙仑和 lestaurtinib，通过抑制 IkappaBalpha 磷酸化来抑制 NF-κB 信号转导。其他药物，如埃替丁、色霉素 A3 和硼替佐米，则利用其他机制。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。我们的结果表明，许多目前批准的药物对 NF-κB 信号转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。对已批准药物的综合分析可深入了解其分子机制，从而为药物再利用提供基础。
