کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2514133 1118450 2009 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Denbinobin inhibits nuclear factor-κB and induces apoptosis via reactive oxygen species generation in human leukemic cells
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی داروشناسی
پیش نمایش صفحه اول مقاله
Denbinobin inhibits nuclear factor-κB and induces apoptosis via reactive oxygen species generation in human leukemic cells
چکیده انگلیسی

Denbinobin, a 1,4-phenanthrenequinone firstly isolated from the stems of Dendrobium moniliforme (Shi-Hu in Chinese medicine), has been reported to exhibit anti-tumoral and anti-inflammatory activities through mechanism(s) not yet fully understood. Because of the critical role of the transcription factor NF-κB and of ROS-induced activation of stress regulated kinases in tumorigenesis, we have investigated the effect of denbinobin on these pathways. We found that denbinobin is a potent inhibitor of TNFα and PMA-induced NF-κB activation, and that it can block the phosphorylation and degradation of IκBα by inhibiting TAK1 activity, an event lying upstream of IKK activation. Moreover, treatment with denbinobin not only elicited apoptotic signalling, including mitochondrial membrane dysfunction, activation of caspases and cleavage of poly(ADP-ribose) polymerase, but also induced intracellular reactive oxygen species (ROS) generation and sustained activation of the mitogen-activated kinases (MAPKs) ERK1+2, p38 and JNK 1+2. The apoptotic effects of denbinobin could be prevented by pre-treatment with the intracellular ROS scavenger N-acetyl-l-cysteine, but not by pharmacological inhibition of MAPKs, suggesting that intracellular ROS generation underlies denbinobin-induced apoptosis, and that this effect takes place in an MAPKs-independent pathway. To define the structural elements critical for these activities, a series of phenanthrenequinones with different substituents in the phenanthrene- and/or in the quinone ring were prepared and assayed for NF-κB inhibition and ROS production. In this way, the major structure–activity relationships and the structural elements critical for the activity of denbinobin could be established.

A proposal model for denbinobin-induced apoptosis in leukemic cellsFigure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 77, Issue 8, 15 April 2009, Pages 1401–1409
نویسندگان
, , , , , , , , ,