Inhibition of IκB kinase-nuclear factor-κB signaling pathway by 3,5-bis(2-flurobenzylidene) piperidin-4-one (EF24), a novel monoketone analog of curcumin
Inhibition of IκB kinase-nuclear factor-κB signaling pathway by 3,5-bis(2-flurobenzylidene) piperidin-4-one (EF24), a novel monoketone analog of curcumin
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DOI：
10.1124/mol.108.046201
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发表时间：
2008-09-01
影响因子：
3.6
通讯作者：
Fu, Haian
中科院分区：
文献类型：
--
作者：
Kasinski, Andrea L.;Du, Yuhong;Fu, Haian
核因子-κ B（NF-κ B）信号通路已被靶向用于治疗包括癌症在内的多种人类疾病。许多天然存在的物质，包括姜黄素，由于其显著的治疗潜力和安全性，已经研究了它们对NF-κ B通路的作用。从姜黄素中合成了一种单酮类化合物3，5-双（2-氟苯亚甲基）哌啶-4-酮（EF 24），具有较强的抗癌活性。在这里，我们报告了EF 24通过直接作用于I κ B激酶（IKK）而有效抑制NF-κ B信号通路的机制。我们证明1）EF 24诱导肺癌、乳腺癌、卵巢癌和宫颈癌细胞死亡，效力比姜黄素高约10倍; 2）EF 24快速阻断NF-κ B B的核转位，IC 50值为1.3 μ M，与姜黄素相比，IC 50值为13 μ M; 3）EF 24有效抑制肿瘤坏死因子（TNF）-α诱导的I κ B磷酸化和降解，表明该化合物在靶向IKK中的作用;和4）EF 24确实直接抑制体外重构系统中IKK的催化活性。我们的研究确定IKK作为EF 24的有效靶点，并为EF 24优于姜黄素的上级活性提供了分子解释。EF 24对TNF-α诱导的NF-κ B B信号传导的有效抑制将EF 24的治疗应用扩展到其它NF-κ B依赖性疾病，包括炎性疾病如类风湿性关节炎。
The nuclear factor-kappa B (NF-kappa B) signaling pathway has been targeted for therapeutic applications in a variety of human diseases, includuing cancer. Many naturally occurring substances, including curcumin, have been investigated for their actions on the NF-kappa B pathway because of their significant therapeutic potential and safety profile. A synthetic mono-ketone compound termed 3,5-bis(2-flurobenzylidene) piperidin-4- one (EF24) was developed from curcumin and exhibited potent anticancer activity. Here, we report a mechanism by which EF24 potently suppresses the NF-kappa B signaling pathway through direct action on I kappa B kinase (IKK). We demonstrate that 1) EF24 induces death of lung, breast, ovarian, and cervical cancer cells, with a potency about 10 times higher than that of curcumin; 2) EF24 rapidly blocks the nuclear translocation of NF-kappa B, with an IC50 value of 1.3 mu M compared with curcumin, with an IC50 value of 13 mu M; 3) EF24 effectively inhibits tumor necrosis factor (TNF)-alpha-induced I kappa B phosphorylation and degradation, suggesting a role of this compound in targeting IKK; and 4) EF24 indeed directly inhibits the catalytic activity of IKK in an in vitro-reconstituted system. Our study identifies IKK as an effective target for EF24 and provides a molecular explanation for a superior activity of EF24 over curcumin. The effective inhibition of TNF-alpha- induced NF-kappa B signaling by EF24 extends the therapeutic application of EF24 to other NF-kappa B-dependent diseases, including inflammatory diseases such as rheumatoid arthritis.