Inhibition of Tumor Necrosis Factor-α-induced Nuclear Translocation and Activation of NF-κB by Dehydroxymethylepoxyquinomicin

Ariga, Akiko; Namekawa, Jun-ichi; Matsumoto, Naoki; Inoue, Jun‐ichiro; Umezawa, Kazuo

doi:10.1074/jbc.m112063200

Cited by 204 publications

(164 citation statements)

References 44 publications

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“…We have shown that DHMEQ inhibits NF-kB at the level of nuclear translocation. 15 In the present study, we demonstrate that topoisomerase inhibitors induce NF-kB in not only H-RS cell lines with wild-type IkBa but also in H-RS cell lines lacking wild-type IkBa by activating IKK and constitutive as well as inducible NF-kB are the molecular target of HL treatment by DHMEQ.…”

supporting

confidence: 57%

“…15 Panepoxydone had been found to inhibit TNF-a-induced activation of NF-kB. We have shown that DHMEQ inhibits NF-kB at the level of nuclear translocation.…”

mentioning

confidence: 79%

“…15,16 Daunorubicin and etoposide were purchased from SIGMA (Toyko, Japan). SN-38, an active metabolite of camptothecin-11, was provided by Yakult (Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

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IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

Watanabe

Dewan

Taira

et al. 2007

Laboratory Investigation

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Constitutive nuclear factor kB (NF-kB) activation characterizes Hodgkin/Reed-Sternberg (H-RS) cells. Blocking constitutive NF-kB has been shown to be a potential strategy to treat Hodgkin lymphoma (HL). Here, for the first time we show that although constitutive NF-kB level of H-RS cell lines is very high, topoisomerase inhibitors further enhance NF-kB activation through IkB kinase activation in not only H-RS cell lines with wild-type IkBa, but also in those with IkBa mutations and lacking wild-type IkBa. Thus, both constitutive and inducible NF-kB are potential targets to treat HL. We also present the data that indicate the involvement of IkBb in NF-kB induction by topoisomerase inhibitors. A new NF-kB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) inhibited constitutive NF-kB activity and induced apoptosis of H-RS cell lines. DHMEQ also inhibited the growth of H-RS cells without significant systemic toxicity in a NOD/SCID/gc null (NOG) mice model. DHMEQ and topoisomerase inhibitors revealed enhancement of apoptosis of H-RS cells by blocking inducible NFkB. Results of this study suggest that both constitutive and inducible NF-kB are molecular targets of DHMEQ in the treatment of HL. The results also indicate that IkBb is involved in NF-kB activation in H-RS cells and IkBb substitutes for IkBa in H-RS cells lacking wild-type IkBa.

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supporting

confidence: 57%

“…15 Panepoxydone had been found to inhibit TNF-a-induced activation of NF-kB. We have shown that DHMEQ inhibits NF-kB at the level of nuclear translocation.…”

mentioning

confidence: 79%

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IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

Watanabe

Dewan

Taira

et al. 2007

Laboratory Investigation

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“…As far as we know, SMMC 7721-CM contains a number of angiogenic factors and cytokines (12), and NF-nB can be activated by many stimuli, including IL-1h (22) and TNF-a (23,24). To identify which factor in SMMC 7721-CM is a major contributor in activating NF-nB through the CD146-induced signal pathway, we tested the effects of IL-1h and TNF-a.…”

Section: Discussionmentioning

confidence: 99%

Anti-CD146 monoclonal antibody AA98 inhibits angiogenesis via suppression of nuclear factor-κB activation

Gao

Zhuang

et al. 2006

Molecular Cancer Therapeutics

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Our previous study showed that an anti-CD146 monoclonal antibody (mAb), AA98, which was raised against the vascular endothelial cells stimulated by a conditioned medium from hepatocarcinoma SMMC 7721 cells (SMMC 7721-CM), inhibited cell migration, angiogenesis, and tumor growth. However, the underlying mechanism was not elucidated. The objective of this study was to understand the mechanism by which mAb AA98 inhibits the endothelial cell migration and angiogenesis that is induced by SMMC 7721-CM. Using confocal imaging and biochemical studies, we found that SMMC 7721-CM induced nuclear factor KB (NF-KB) activation through the upstream p38 mitogen-activated protein kinase pathway, leading to the up-regulation of matrix metalloproteinase 9 and intercellular adhesion molecule 1 expression. Interestingly, all these activities stimulated by SMMC 7721-CM could be effectively inhibited by mAb AA98 in a dose-and time-dependent manner. Our data showed that the engagement of mAb AA98 with membrane protein CD146 inhibited p38 mitogen-activated protein kinase phosphorylation, suppressed NF-KB activation, and downregulated matrix metalloproteinase 9 and intercellular adhesion molecule 1 expression, suggesting that the suppression of NF-KB is a critical point for the inhibitory function of mAb AA98 on endothelial cell migration, angiogenesis, and tumor metastasis. These results will provide clues for a better understanding of the mechanisms underlying tumor angiogenesis as well as antiangiogenesis therapy.

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“…These observations indicated DHMEQ specifically inhibited the NF-κB activating pathway. (18) DHMEQ also inhibited TPA-induced NF-κB activation in Jurkat cells. TPA is considered to activate IKK through the activation of protein kinase C. Therefore, it was suggested that DHMEQ inhibits the NF-κB activation at a level that is downstream of IKK.…”

Section: Naturally Occurring Nf-κ κ κ κB Inhibitors and Discovery Of mentioning

confidence: 83%

Inhibition of tumor growth by NF‐κB inhibitors

Umezawa¹

2006

Cancer Science

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NF-κ κ κκB is a transcription factor that induces inflammatory cytokines and anti-apoptotic proteins. NF-κ κ κ κB is often constitutively activated in human cancers and leukemias, which might increase the malignant character of neoplastic diseases. Therefore, NF-κ κ κ κB inhibitors might be useful as anticancer agents. Our research team designed a new NF-κ κ κ κB inhibitor that is based on the structure of the antibiotic epoxyquomicin C isolated from a microorganism. The designed compound, DHMEQ, inhibited the ligand-induced activation of NF-κ κ κ κB, and it also inhibited the constitutively activated NF-κ κ κ κB in cancer cells. DHMEQ is a unique inhibitor of NF-κ κ κ κB that acts at the level of the nuclear translocation. It inhibited both canonical and non-canonical NF-κ κ κ κB activating pathways. It inhibited various carcinomas and leukemias in animal models without any toxicity, and might be useful as an anticancer agent. Structure and function of NF-κ κ κ κB I n 1986, NF-κB was found to be a nucleoprotein that is bound to the enhancer region of the immunoglobulin κ chain gene.(NF-κB is typically a heterodimer that consists of the p65 (RelA) and p50 proteins.(2) NF-κB might be various heterodimers or homodimers. The NF-κB family of proteins includes p65, p50, p52, c-Rel, RelB, v-Rel, Dorsal, and Dif. Dorsal and Dif are proteins involved in the Drosophila immune system. The Rel subfamily, p50, and p52 proteins contain the Rel homology domain that consists of approximately 300 amino acids. The Rel homology domain is essential for dimerization and binding to DNA, as well as for IκB to bind to NF-κB in order to keep the latter inactive.NF-κB is the transcription factor that binds to the κB sequence. It promotes the transcription of inflammatory cytokines such as IL-1, IL-2, IL-6, IL-8, IL-10 (often suppresses inflammation), IL-12, and TNF-α, cell adhesion moleculers such as E-selectin, ICAM-1, and VCAM-1, and viral proteins. Therefore, NF-κB is primarily an inducer of inflammatory cytokines.(3,4) Its inhibitors could be useful as anti-inflammatory agents. Moreover, NF-κB also induces transcription of anti-apoptotic proteins including IAPs, FLIP, and Bcl-XL. It also induces cyclin D1 that promotes cell growth. Therefore, the NF-κB function inhibitors might also be useful as anticancer agents.Signal transduction pathway of NF-κ κ κ κB activation NF-κB is usually inactive in the cytoplasm without stimulation. As shown in Figure 1, it is activated by extracellular signals such as TNF-α, IL-1, LPS, lipopeptides, and tumor promoters such as phorbol esters.(1,5) The signal transduction pathways from the TNF-α receptor to NF-κB activation have been extensively studied.(6) There are TNFR1 and TNFR2, but TNF-α mainly acts through TNFR1. The cytoplasmic region of TNFR1 contains the death domain that binds to TRADD. For induction of apoptosis, TRADD then activates Fas-associated death domain-containing molecule, which in turn activates caspase 8. For activation of NF-κB, TRADD recruits receptor-interacting protein and TRA...

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Inhibition of Tumor Necrosis Factor-α-induced Nuclear Translocation and Activation of NF-κB by Dehydroxymethylepoxyquinomicin

Abstract: We previously designed and synthesized an NF-B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), that showed anti-inflammatory activity in vivo. In the present study we looked into its mechanism of inhibi-

Cited by 204 publications

References 44 publications

IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

Anti-CD146 monoclonal antibody AA98 inhibits angiogenesis via suppression of nuclear factor-κB activation

Inhibition of tumor growth by NF‐κB inhibitors

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