Synthesis of NF-κB activation inhibitors derived from epoxyquinomicin C

Matsumoto, Naoki; Ariga, Akiko; To-e, Sakino; Nakamura, Hikaru; Agata, Naoki; Hirano, Shin‐ichi; Inoue, Jun‐ichiro; Umezawa, Kazuo

doi:10.1016/s0960-894x(00)00114-1

Cited by 156 publications

(110 citation statements)

References 8 publications

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“…Several strategies for reversing NF-B activation have been employed, including inhibition of tyrosine phosphorylation, NF-B translocation to nucleus, degradation, IKK⅐I-B␣ complex formation, IKK activation, and cyclooxygenase-2 activity. NF-B translocation into the nucleus can be blocked by a synthetic compound, dehydroxymethylepoxyquinomicin, which is a derivative of 2,5-dimethoxyaniline (24). Proteasome inhibition has broad application, because inhibition of the proteosome affects the accumulation of cyclins, cyclin-dependent kinase inhibitors, transcriptional factors, and tumor suppressors as well as I-B␣ (25).…”

Section: Discussionmentioning

confidence: 99%

Transglutaminase 2 Mediates Polymer Formation of I-κBα through C-terminal Glutamine Cluster

Park

Kim

et al. 2006

Journal of Biological Chemistry

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Recently we reported that transglutaminase 2 (TGase 2) activates nuclear factor-B (NF-B) independently of I-B kinase (IKK) activation, by inducing cross-linking and protein polymer formation of inhibitor of nuclear factor-B␣ (I-B␣). TGase 2 catalyzes covalent isopeptide bond formation between the peptide bound-glutamine and the lysine residues. Using matrix-assisted laser desorption ionization time-of-flight mass spectra analysis of I-B␣ polymers cross-linked by TGase 2, as well as synthetic peptides in an in vitro competition assay, we identified a glutamine cluster at the C terminus of I-B␣ (amino acids 266 -268) that appeared to play a key role in the formation of I-B␣ polymers. Although there appeared to be no requirement for specific lysine residues, we found a considerably higher preference for the use of lysine residues at positions 21, 22, and 177 in TGase 2-mediated cross-linking of I-B␣. We demonstrated that synthetic peptides encompassing the glutamine cluster at amino acid positions 266 -268 reversed I-B␣ polymerization in vitro. Furthermore, the depletion of free I-B␣ in EcR/TG cells was completely rescued in vivo by transfection of mutant I-B␣s in glutamine sites (Q266G, Q267G, and Q313G) as well as in a lysine site (K177G). These findings provide additional clues into the mechanism by which TGase 2 contributes to the inflammatory process via activation of NF-B. NF-B2 belongs to a family of transcription factors that contribute to the progress of inflammatory disease and the development of cancer through the regulation of specific gene expression (1). Under normal cellular conditions, NF-B is retained in an inactive state in the cytosol through its association with I-B␣ (2). Exposure to certain stresses, such as lipopolysaccharide or tumor necrosis factor-␣ (TNF-␣), activates signaling pathways that ultimately result in ubiquitination of I-B␣, through a mechanism that involves IKK-dependent phosphorylation of I-B␣ (3). Proteosome-mediated degradation of ubiquitinated I-B␣ releases NF-B, which then translocates to the nucleus and becomes active (4). The development of therapeutics that block the degradation of I-B␣ represents a promising approach to treating many of the diseases in which NF-B plays a role (5). For example, IKK-dependent stress signaling has been shown to deplete I-B␣ through phosphorylation of serine 32 and serine 36 (6 -8), and administration of peptides carrying the same amino acid sequences as the I-B␣ phosphorylation sites selectively inhibits I-B␣ phosphorylation and degradation and subsequent activation of NF-B (9).Recently, we identified an IKK-independent mechanism of NF-B activation through TGase 2-mediated cross-linking of I-B␣ (10, 11). TGase 2 (EC 2.3.2.13) is an enzyme that catalyzes the formation of a strong covalent bond between peptide-bound glutamine and lysine residues, resulting in protein cross-linking and the formation of protein polymers (12). TGase 2-mediated polymerization of I-B␣ depletes free I-B␣ from the cytosol, resulting in the activation of NF-B (11). ...

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Section: Discussionmentioning

confidence: 99%

Transglutaminase 2 Mediates Polymer Formation of I-κBα through C-terminal Glutamine Cluster

Park

Kim

et al. 2006

Journal of Biological Chemistry

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“…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%

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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“…DHMEQ inhibited rheumatoid arthritis, (15,40) renal inflammation, (41) and cancer cachexia (42) in animals. In addition to these antiinflammatory effects, DHMEQ showed potent anticancer activity in various animal models, as shown in Figure 8.…”

Section: Antineoplastic Activity Of Dhmeq In Vivomentioning

confidence: 94%

“…The designed compound, DHMEQ, was synthesized and did inhibit this activation in human T cell leukemia Jurkat cells. (15) We tested the effect of DHMEQ and its weaker synthetic analog, DHM3EQ, on TNF-α-induced NF-κB activation in human T cell leukemia Jurkat cells. DHMEQ was more potent in inhibiting NF-κB and less toxic than DHM3EQ in Jurkat cells.…”

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

confidence: 99%

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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Synthesis of NF-κB activation inhibitors derived from epoxyquinomicin C

Cited by 156 publications

References 8 publications

Transglutaminase 2 Mediates Polymer Formation of I-κBα through C-terminal Glutamine Cluster

Transglutaminase 2 Mediates Polymer Formation of I-κBα through C-terminal Glutamine Cluster

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

Inhibition of tumor growth by NF‐κB inhibitors

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