Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tylophorine and related natural compounds exhibit potent antitumor activities. We previously showed that PBT-1, a synthetic C9-substituted phenanthrene-based tylophorine (PBT) derivative, significantly inhibits growth of various cancer cells. In this study, we further explored the mechanisms and potential of PBT-1 as an anticancer agent. PBT-1 dose-dependently suppressed colony formation and induced cell cycle G2/M arrest and apoptosis. DNA microarray and pathway analysis showed that PBT-1 activated the apoptosis pathway and mitogen-activated protein kinase signaling. In contrast, PBT-1 suppressed the nuclear factor kappaB (NF-kappaB) pathway and focal adhesion. We further confirmed that PBT-1 suppressed Akt activation accelerated RelA degradation via IkappaB kinase-alpha and down-regulated NF-kappaB target gene expression. The reciprocal recruitment of RelA and RelB on COX-2 promoter region led to down-regulation of transcriptional activity. We conclude that PBT-1 induces cell cycle G2/M arrest and apoptosis by inactivating Akt and by inhibiting the NF-kappaB signaling pathway. PBT-1 may be a good drug candidate for anticancer chemotherapy.
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PMID:Phenanthrene-based tylophorine-1 (PBT-1) inhibits lung cancer cell growth through the Akt and NF-kappaB pathways. 1928 64

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-kappaB 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 TNFalpha and PMA-induced NF-kappaB activation, and that it can block the phosphorylation and degradation of IkappaBalpha 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-kappaB 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.
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PMID:Denbinobin inhibits nuclear factor-kappaB and induces apoptosis via reactive oxygen species generation in human leukemic cells. 1942 79