Novel mechanism of inhibition of nuclear factor-κB DNA-binding activity by diterpenoids isolated from Isodon rubescens
Novel mechanism of inhibition of nuclear factor-κB DNA-binding activity by diterpenoids isolated from Isodon rubescens
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DOI：
10.1124/mol.105.012765
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发表时间：
2005-08-01
影响因子：
3.6
通讯作者：
Cheng, YC
中科院分区：
文献类型：
--
作者：
Leung, CH;Grill, SP;Cheng, YC
能够阻断核因子-κ B（NF-κ B）活化的特异性抑制剂的开发是用于治疗癌症、自身免疫和炎性疾病的方法。从冬凌草（Isodon rubescens）中分得2个二萜类化合物，分别为冬凌草甲素（oridonin）、短叶乙素（ponicidin）、新冬宁A和新冬宁B。发现这些化合物是NF-κ B转录活性及其下游靶点环氧合酶-2和诱导型一氧化氮合酶表达的有效抑制剂。二萜类化合物对NF-κ B的作用机制相似，但也发现了显著差异。所有的二萜类化合物直接干扰NF-κ B与其应答DNA序列的DNA结合活性。冬凌草甲素和Ponicidin对NF-κ B从细胞质到细胞核的易位具有额外的影响，而不影响I κ B-α磷酸化和降解。这些化合物对NF-κ B B与共有DNA序列相互作用的影响是独特的。当NF-κ B与不同的DNA序列结合时，观察到不同的抑制作用。p65/p65和p50/p50同源二聚体以及p65/p50异源二聚体与其响应DNA的结合均被抑制。NF-κ B-DNA相互作用的动力学研究表明，二萜类化合物降低B-max（app），但对K-d app没有影响。这表明，这类化合物与p65和p50亚基在DNA结合位点以外的位点相互作用，随后调节转录因子对具有不同NF-κ B结合序列的DNA的结合亲和力。因此，二萜类化合物结构可以作为开发更有效和选择性的NF-κ B抑制剂的支架，靶向调节基因转录。
The development of specific inhibitors that can block nuclear factor-kappa B (NF-kappa B) activation is an approach for the treatment of cancer, autoimmune, and inflammatory diseases. Several diterpenoids, oridonin, ponicidin, xindongnin A, and xindongnin B were isolated from the herb Isodon rubescens. These compounds were found to be potent inhibitors of NF-kappa B transcription activity and the expression of its downstream targets, cyclooxygenase-2 and inducible nitric-oxide synthase. The mechanisms of action of the diterpenoids against NF-kappa B are similar, but significant differences were also identified. All of the diterpenoids directly interfere with the DNA-binding activity of NF-kappa B to its response DNA sequence. Oridonin and ponicidin have an additional impact on the translocation of NF-kappa B from the cytoplasm to nuclei without affecting I kappa B-alpha phosphorylation and degradation. The effect of these compounds on the interaction of NF-kappa B with consensus DNA sequences is unique. Different inhibitory effects were observed when NF-kappa B bound to various DNA sequences. Both p65/p65 and p50/p50 homodimers, as well as p65/p50 heterodimer association with their responsive DNA, were inhibited. Kinetic studies on NF-kappa B-DNA interaction indicate that the diterpenoids decrease the B-max (app) but have no effect on K-d app. This suggests that this class of compounds interacts with both p65 and p50 subunits at a site other than the DNA binding site and subsequently modulates the binding affinity of the transcription factor toward DNA with different NF-kappa B binding sequences. The diterpenoid structure could therefore serve as a scaffold for the development of more potent and selective NF-kappa B inhibitors that target regulated gene transcription.