Synthesis and Structure–Activity Relationship of Dehydroxymethylepoxyquinomicin Analogues as Inhibitors of NF-κB Functions

Chaicharoenpong, Chanya; Kato, Kuniki; Umezawa, Kazuo

doi:10.1016/s0968-0896(02)00315-2

Cited by 16 publications

(9 citation statements)

References 11 publications

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“…For example lactacystin blocks the nuclear translocation of NFκB, by maintaining IκB-bound NFκB in the cytoplasm [49], while NO and aspirin prevent its nuclear import by inhibiting IκB phosphorylation, thus maintaining high concentration of IκB available for binding the NFκB in the cytoplasm [49]. Downstream in the signaling pathway, a rather direct inhibition of nuclear translocation of NFκB appeared to be exerted by dehydroxymethylepoxyquinomicin (DHMEQ) in leukemia Jurkat cells [52,53] and in an advanced human bladder cancer cell line [54].…”

Section: Subcellular Trafficking Of Heat-shock Proteinsmentioning

confidence: 99%

Nuclear Translocation During the Cross-Talk Between Cellular Stress, Cell Cycle and Anticancer Agents

Tiligada¹

2006

CMC

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The function of many endogenous molecules in all eukaryotic cells depends on their subcellular localisation, being active when localized in one cellular compartment and inactive in another. Translocation or re-localization of mislocalized components in the optimal subcellular site may contribute to the development of novel cancer therapies and to the re-evaluation of conventional treatment. For instance, various agents are able to entrap cytoplasmic anti-apoptotic pathways to the nucleus, thus activating apoptosis. Moreover, amongst the factors identified so far, the optimal location of the tumor suppressor p53 for promoting cell arrest and apoptosis seems to be the nucleus, while the nuclear factor kappa B (NFkappaB) is desirable to stay in the cytoplasm. Thus, the mechanisms of nuclear translocation of endogenous signaling components, like p53, NFkappaB and various heat shock proteins (HSPs), may serve as targets for pharmacological intervention, without excluding the possible role of uptake and active transport into the nucleus of extracellular proteins.

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Section: Subcellular Trafficking Of Heat-shock Proteinsmentioning

confidence: 99%

Nuclear Translocation During the Cross-Talk Between Cellular Stress, Cell Cycle and Anticancer Agents

Tiligada¹

2006

CMC

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“…[25]. Most NF-κB inhibitors inhibit IκBα phosphorylation, whereas DHMEQ inhibits nuclear translocation of p65 protein, a component of NF-κB [25,14].…”

Section: Discussionmentioning

confidence: 99%

Dehydroxymethylepoxyquinomicin Inhibits Expression and Production of Inflammatory Mediators in Interleukin-1β-induced Human Chondrocytes

Cardile

Frasca²,

Libra³

et al. 2010

Cell Physiol Biochem

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The present research was carried out to determine the effects of a nuclear factor-kappaB (NF-ĸB) inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), derivative of the antibiotic epoxyquinomicin C, on normal human chondrocytes treated with interleukin-1β (IL-1β). This is a cell model particularly useful to reproduce the mechanisms involved in degenerative arthropathies, where oxidative-inflammatory stress determines a progressive destruction of the articular cartilaginous tissue. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and inter-cellular adhesion molecule (ICAM)-1 was evaluated through Western blot analysis. The release of chemokines like monocyte chemoattractant protein-1 (MCP-1), regulated upon normal activation T-cell expressed and secreted (RANTES), and interleukin-8 (IL-8) were determined by ELISA assays. DHMEQ acts as a potent inhibitor of iNOS and COX-2 gene expression while also suppressing the production of nitrite in human chondrocytes. In addition, DHMEQ induces a significant dose-dependent decrease in ICAM expression, MCP-1, RANTES, and IL-8 release. DHMEQ helps to decrease the expression and production of pro-inflammatory mediators in IL-1β-induced chondrocytes. DHMEQ may become a therapeutic agent for treatment of chondro-degenerative diseases.

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“…and, like epoxyquinomicin C, retains the cyclohexylepoxydone moiety. In addition, the 2‐hydroxyl group of the benzamide ring is essential for the activity of DHMEQ 26 . Thus, DHMEQ is likely to inhibit both the canonical and non‐canonical activation of NF‐κB by inhibiting the nuclear translocation of both RelA/p50 and RelB p52 15 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the 2-hydroxyl group of the benzamide ring is essential for the activity of DHMEQ. 26 Thus, DHMEQ is likely to inhibit both the canonical and non-canonical activation of NF-jB by inhibiting the nuclear translocation of both RelA ⁄ p50 and RelB p52. 15 Dehydroxymethylepoxyquinomicin inhibits the TNF-a-induced NF-jB binding activity, but not the phosphorylation or degradation of IkB.…”

Section: Discussionmentioning

confidence: 99%

Dehydroxymethylepoxyquinomicin, a novel nuclear factor‐κB inhibitor, prevents inflammatory injury induced by interferon‐γ and histamine in NCTC 2544 keratinocytes

Cardile¹,

Libra²,

Caggia³

et al. 2010

Clin Exp Pharma Physio

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1. The novel nuclear factor (NF)-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) is a derivative of the antibiotic epoxyquinomicin C from Amycolatopsis sp. that has been found to inhibit tumour necrosis factor (TNF)-alpha-induced activation of NF-kappaB by suppressing nuclear translocation of NF-kappaB. The aim of the present study was to determine the effects of DHMEQ on interferon (IFN)-gamma- and histamine-activated NCTC 2544 keratinocytes. 2. Keratinocytes were stimulated or not with 200 U/mL IFN-gamma and 10(-4) mol/L histamine in the absence or presence of different concentrations of DHMEQ (1, 5 and 10 microg/mL) or hydrocortisone (10(-5) mol/L), which was used as a reference anti-inflammatory drug. After 48 h, each sample was tested for the presence of intercellular adhesion molecule (ICAM)-1 by western blot analysis, as well as for the release of monocyte chemoattractant protein (MCP)-1, RANTES and interleukin (IL)-8 using specific sandwich ELISAs. To verify the effect of DHMEQ on cell viability of non-stimulated NCTC 2544 keratinocytes, the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used. 3. The results showed that 10 microg/mL DHMEQ potently inhibited ICAM-1 production (by 50%), as well as the release of MCP-1 (to 25% of control), RANTES (to 5% of control) and IL-8 (to 2% of control). The results of the MTT assay indicated that DHMEQ has no effect on cell viability. 4. In conclusion, DHMEQ inhibits the IFN-gamma- and histamine-induced activation of the keratinocyte cell line NCTC 2544. The anti-inflammatory effects of DHMEQ could be exploited by applying the drug topically alone or in combination with sub-toxic concentrations of anti-inflammatory drugs to producer a synergistic effect.

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Synthesis and Structure–Activity Relationship of Dehydroxymethylepoxyquinomicin Analogues as Inhibitors of NF-κB Functions

Cited by 16 publications

References 11 publications

Nuclear Translocation During the Cross-Talk Between Cellular Stress, Cell Cycle and Anticancer Agents

Nuclear Translocation During the Cross-Talk Between Cellular Stress, Cell Cycle and Anticancer Agents

Dehydroxymethylepoxyquinomicin Inhibits Expression and Production of Inflammatory Mediators in Interleukin-1β-induced Human Chondrocytes

Dehydroxymethylepoxyquinomicin, a novel nuclear factor‐κB inhibitor, prevents inflammatory injury induced by interferon‐γ and histamine in NCTC 2544 keratinocytes

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