Umezawa Kazuo, Chaicharoenpong Chanya
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan.
Mol Cells. 2002 Oct 31;14(2):163-7.
NF-kappaB is a transcription factor that induces inflammatory cytokines and anti-apoptotic proteins. We designed a new NF-kappaB inhibitor that is based on the structe of the antibiotic epoxyquinomicin C. The designed compound, dehydroxymethyl-epoxyquinomicin (DHMEQ), inhibited the TNF-alpha-induced activation of NF-kappaB, and showed an anti-arthritic effect in mice. Recently, we looked into its mechanism of inhibition. DHMEQ inhibited the TNF-alpha-induced cellular DNA binding of nuclear NF-kappaB, but not the phosphorylation or degradation of I-kappaB. Moreover, DHMEQ inhibited the TNF-alpha-induced nuclear accumulation of p65, a component of NF-kappaB. On the other hand, DHMEQ did not inhibit the nuclear transport of Smad2 and the large T antigen. Also, it did not inhibit the TNF-alpha-induced activation of JNK, but synergistically induced apoptosis with TNF-alpha in human T cell leukemia Jurkat cells. Therefore, DHMEQ specifically inhibited the NF-kappaB-activating pathway in the TNF-alpha-treated cells. Taken together, our data show that DHMEQ is a unique inhibitor of NF-kappaB that acts at the level of the nuclear translocation. It may be useful as an anti-inflammatory and anticancer agent.
核因子-κB是一种可诱导炎性细胞因子和抗凋亡蛋白的转录因子。我们基于抗生素环氧喹霉素C的结构设计了一种新型核因子-κB抑制剂。所设计的化合物脱羟甲基环氧喹霉素（DHMEQ）可抑制肿瘤坏死因子-α（TNF-α）诱导的核因子-κB激活，并在小鼠中显示出抗关节炎作用。最近，我们研究了其抑制机制。DHMEQ可抑制TNF-α诱导的核因子-κB与细胞DNA的结合，但不抑制I-κB的磷酸化或降解。此外，DHMEQ可抑制TNF-α诱导的核因子-κB组分p65的核内蓄积。另一方面，DHMEQ不抑制Smad2和大T抗原的核转运。而且，它不抑制TNF-α诱导的JNK激活，但在人T细胞白血病Jurkat细胞中与TNF-α协同诱导凋亡。因此，DHMEQ特异性抑制TNF-α处理细胞中的核因子-κB激活途径。综上所述，我们的数据表明DHMEQ是一种独特的核因子-κB抑制剂，作用于核转位水平。它可能作为一种抗炎和抗癌药物发挥作用。
