Eriocalyxin B inhibits nuclear factor-κB activation by interfering with the binding of both p65 and p50 to the response element in a noncompetitive manner
Eriocalyxin B inhibits nuclear factor-κB activation by interfering with the binding of both p65 and p50 to the response element in a noncompetitive manner
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DOI：
10.1124/mol.106.028480
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发表时间：
2006-12-01
影响因子：
3.6
通讯作者：
Cheng, Yung-Chi
中科院分区：
文献类型：
--
作者：
Leung, Chung-Hang;Grill, Susan P.;Cheng, Yung-Chi
核因子 kappa B (NF-kappa B) 已被认为在细胞存活和炎症过程中发挥着关键作用。它已成为治疗癌症、炎症和自身免疫性疾病的强力药物开发的目标。在这里，我们描述了一种有效的 NF-κ B 抑制剂，eriocalyxin B (Eri-B)，一种从 Isodon eriocalyx 中分离出来的 ent-kauranoid，一种抗炎药物。两种 α,β-不饱和酮的存在使该化合物在测试的对映贝壳杉烷类化合物中具有独特性。 Eri-B 抑制 NF-kappa B 转录活性，但不抑制 cAMP 反应元件结合蛋白的转录活性。它抑制巨噬细胞和肝癌细胞中由肿瘤坏死因子-α或脂多糖诱导的 NF-kappa B 下游基因产物的转录，包括环氧合酶-2 和诱导型一氧化氮合酶。染色质免疫沉淀实验表明，Eri-B 在体内选择性阻断 NF-kappa B 与反应元件的结合，而不影响转录因子的核转位。内源性 p65 蛋白的下调使细胞对化合物的作用敏感。此外，体外结合测定表明，Eri-B 以非竞争性方式可逆地干扰 p65 和 p50 亚基与 DNA 的结合。总之，这项研究揭示了一种有效的 NF-κ B 抑制剂的新作用，可用于治疗多种 NF-κ B 相关疾病。此类化合物结构的修饰成为控制该化合物针对不同细胞信号通路的行为的关键。
Nuclear factor-kappa B (NF-kappa B) has been recognized to play a critical role in cell survival and inflammatory processes. It has become a target for intense drug development for the treatment of cancer, inflammatory, and autoimmune diseases. Here, we describe a potent NF-kappa B inhibitor, eriocalyxin B (Eri-B), an ent-kauranoid isolated from Isodon eriocalyx, an anti-inflammatory remedy. The presence of two alpha,beta-unsaturated ketones give this compound the uniqueness among the ent-kauranoids tested. Eri-B inhibited the NF-kappa B transcriptional activity but not that of cAMP response element-binding protein. It suppressed the transcription of NF-kappa B downstream gene products including cyclooxygenase-2 and inducible nitric-oxide synthase induced by tumor necrosis factor-alpha or lipopolysaccharide in macrophages and hepatocarcinoma cells. Chromatin immunoprecipitation assay indicated that Eri-B selectively blocked the binding between NF-kappa B and the response elements in vivo without affecting the nuclear translocation of the transcription factor. Down-regulation of the endogenous p65 protein sensitized the cells toward the action of the compound. Furthermore, in vitro binding assays suggested that Eri-B reversibly interfered with the binding of p65 and p50 subunits to the DNA in a noncompetitive manner. In summary, this study reveals the novel action of a potent NF-kappa B inhibitor that could be potentially used for the treatment of a variety of NF-kappa B-associated diseases. Modification of the structure of this class of compounds becomes the key to the control of the behavior of the compound against different cellular signaling pathways.