Rocaglamide derivatives are potent inhibitors of NF-κB activation in T-cells

被引:77
作者
Baumann, B
Bohnenstengel, F
Siegmund, D
Wajant, H
Weber, C
Herr, I
Debatin, KM
Proksch, P
Wirth, T [1 ]
机构
[1] Univ Ulm, Dept Chem Phys, D-89081 Ulm, Germany
[2] Univ Ulm, Dept Internal Med 1, D-89081 Ulm, Germany
[3] Univ Childrens Hosp, D-89075 Ulm, Germany
[4] Univ Dusseldorf, Inst Pharmaceut Biol, D-40225 Dusseldorf, Germany
[5] Univ Stuttgart, Inst Cell Biol & Immunol, D-70569 Stuttgart, Germany
[6] German Canc Res Ctr, D-69120 Heidelberg, Germany
关键词
D O I
10.1074/jbc.M208003200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Crude extracts from different Aglaia species are used as anti-inflammatory remedies in the traditional medicine of several countries from Southeast Asia. Because NF-kappaB transcription factors represent key regulators of genes involved in immune and inflammatory responses, we supposed that the anti-inflammatory effects of Aglaia extracts are mediated by the inhibition of NF-kappaB activity. Purified compounds of Aglaia species, namely 1H-cyclopenta[b]benzofuran lignans of the rocaglamide type as well as one aglain congener were tested for their ability to inhibit NF-kappaB activity. We show that a group of rocaglamides represent highly potent and specific inhibitors of tumor necrosis factor-alpha (TNFalpha) and phorbol 12-myristate 13-acetate (PMA)-induced NF-kappaB-dependent reporter gene activity in Jurkat T cells with IC50 values in the nanomolar range. Some derivatives are less effective, and others are completely inactive. Rocaglamides are able to suppress the PMA-induced expression of NF-kappaB target genes and sensitize leukemic T cells to apoptosis induced by TNFalpha, cisplatin, and gamma-irradiation. The suppression of NF-kappaB activation correlated with the inhibition of induced IkappaBalpha degradation and IkappaBalpha kinase activation. The level of interference was determined and found to be localized upstream of the IkappaB kinase complex but downstream of the TNF receptor-associated protein 2. Our data suggest that rocaglamide derivatives could serve as lead structures in the development of anti-inflammatory and tumoricidal drugs.
引用
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页码:44791 / 44800
页数:10
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