Anticancer agent CHS 828 suppresses nuclear factor‐κB activity in cancer cells through downregulation of IKK activity

Olsen, L. S.; Hjarnaa, Pernille-Julia Vig; Latini, Scilla; Holm, Pernille; Larsson, Rolf; Bramm, E.; Binderup, Lise; Madsen, Mogens Winkel

doi:10.1002/ijc.20255

Cited by 43 publications

(40 citation statements)

References 37 publications

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“…4B). In addition, and consistent with activated JNK signaling, we also observed high concentrations of the phosphorylated forms of the AP-1 transcription factors subunits c-Jun and Atf2 (6,7,24) in the nuclear extracts of CARD11(L225LI)-transgenic cells (Fig. 4C).…”

Section: Card11(l225li)-induced Lymphoproliferation Is Strictly Depensupporting

confidence: 78%

“…Canonical NF-κB signaling is regulated by IκB kinase β (IKKβ), which induces proteolytic degradation of inhibitory IκB proteins by their phosphorylation and thereby allows translocation of NF-κB transcription factors into the nucleus. Although small molecule inhibitors of IKKβ efficiently block the growth of ABC-DLBCL cells in vitro (5), clinical trials failed due to highly toxic side effects (NCT00003979) (6,7).…”

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confidence: 99%

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Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Knies

Alankus

Weilemann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The aggressive activated B cell-like subtype of diffuse large B-cell lymphoma is characterized by aberrant B-cell receptor (BCR) signaling and constitutive nuclear factor kappa-B (NF-κB) activation, which is required for tumor cell survival. BCR-induced NF-κB activation requires caspase recruitment domain-containing protein 11 (CARD11), and CARD11 gain-of-function mutations are recurrently detected in human diffuse large B-cell lymphoma (DLBCL). To investigate the consequences of dysregulated CARD11 signaling in vivo, we generated mice that conditionally express the human DLBCL-derived CARD11(L225LI) mutant. Surprisingly, CARD11(L225LI) was sufficient to trigger aggressive B-cell lymphoproliferation, leading to early postnatal lethality. CARD11(L225LI) constitutively associated with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) to simultaneously activate the NF-κB and c-Jun N-terminal kinase (JNK) signaling cascades. Genetic deficiencies of either BCL10 or MALT1 completely rescued the phenotype, and pharmacological inhibition of JNK was, similar to NF-κB blockage, toxic to autonomously proliferating CARD11(L225LI)-expressing B cells. Moreover, constitutive JNK activity was observed in primary human activated B cell-like (ABC)-DLBCL specimens, and human ABC-DLBCL cells were also sensitive to JNK inhibitors. Thus, our results demonstrate that enforced activation of CARD11/BCL10/MALT1 signaling is sufficient to drive transformed B-cell expansion in vivo and identify the JNK pathway as a therapeutic target for ABC-DLBCL.

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Section: Card11(l225li)-induced Lymphoproliferation Is Strictly Depensupporting

confidence: 78%

mentioning

confidence: 99%

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Knies

Alankus

Weilemann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…TPCA-1 is an inhibitor of IKKα/β and selectively inhibits IKKβ 20-fold more than IKKα [18] . A final concentration of 0.1% (v/v) DMSO had no influence on LPS-stimulated NF-κB/p65 translocation to the nucleus, as reported previously (as shown in Figure 5A-5a, 5b, 5c) [19,20] . Immunoblot analysis showed that the levels of npg NF-κB/p65 proteins in nuclear extracts treated by lobolide were markedly decreased compared to those treated only by LPS ( Figure 5B).…”

Section: Lobolide Attenuated Nf-κb/p65 Nuclear Translocationsupporting

confidence: 84%

Lobolide, a diterpene, blockades the NF-κB pathway and p38 and ERK MAPK activity in macrophages in vitro

Chen

et al. 2012

Acta Pharmacol Sin

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Aim: Recent studies have shown that constitutive activation of the nuclear factor κB (NF-κB) plays a key role in chronic inflammation and cancers. The aim of this study was to characterize lobolide, a cembrane diterpene, as a drug candidate targeting the NF-κB signaling pathway. Methods: A HEK 293/NF-κB-Luc stable cell line was constructed to evaluate the effect of lobolide on NF-κB activation. THP-1 human monocytes and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were tested. Lipopolysaccharide (LPS)-induced TNFα and IL-1β production and activation of the TAK1-IKK-NF-κB pathway were studied using ELISA and Western blot analysis. Results: In HEK 293/NF-κB-Luc stable cells, lobolide (0.19-50 μmol/L) inhibited NF-κB activation in a concentration-dependent manner with an IC 50 value of 4.2±0.3 μmol/L. Treatment with lobolide (2.5-10 μmol/L) significantly suppressed LPS-induced production of TNFα and IL-1β in both THP-1 cells and PBMCs. In THP-1 cells, the suppression was partially caused by blockade of the translocation of NF-κB from the cytoplasm to the nucleus via affecting the TAK1-IKK-NF-κB pathway and p38 and ERK MAPK activity. Conclusion: Lobolide is a potential inhibitor of the NF-κB pathway, which blocks the translocation of NF-κB from the cytoplasm to the nucleus. Lobolide inhibits LPS-stimulated TNFα and IL-1β release, suggesting that the compound might be an anti-inflammatory compound.

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“…The antitumor activity of GMX1778 has been widely studied since its discovery (1,11,(19)(20)(21)24), but positive identification of the molecular target and the mechanism of action of GMX1778 has been elusive. Here, we demonstrate that GMX1778 exerts its antitumor activity via its potent and selective antagonism of NAD ϩ biosynthesis.…”

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confidence: 99%

The Small Molecule GMX1778 Is a Potent Inhibitor of NAD⁺ Biosynthesis: Strategy for Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors

Watson

Roulston

Bélec

et al. 2009

Molecular and Cellular Biology

205

236

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GMX1777 is a prodrug of the small molecule GMX1778, currently in phase I clinical trials for the treatment of cancer. We describe findings indicating that GMX1778 is a potent and specific inhibitor of the NAD ؉ biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT). Cancer cells have a very high rate of NAD ؉ turnover, which makes NAD ؉ modulation an attractive target for anticancer therapy. Selective inhibition by GMX1778 of NAMPT blocks the production of NAD ؉ and results in tumor cell death. Furthermore, GMX1778 is phosphoribosylated by NAMPT, which increases its cellular retention. The cytotoxicity of GMX1778 can be bypassed with exogenous nicotinic acid (NA), which permits NAD ؉ repletion via NA phosphoribosyltransferase 1 (NAPRT1). The cytotoxicity of GMX1778 in cells with NAPRT1 deficiency, however, cannot be rescued by NA. Analyses of NAPRT1 mRNA and protein levels in cell lines and primary tumor tissue indicate that high frequencies of glioblastomas, neuroblastomas, and sarcomas are deficient in NAPRT1 and not susceptible to rescue with NA. As a result, the therapeutic index of GMX1777 can be widended in the treatment animals bearing NAPRT1-deficient tumors by coadministration with NA. This provides the rationale for a novel therapeutic approach for the use of GMX1777 in the treatment of human cancers.

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Anticancer agent CHS 828 suppresses nuclear factor‐κB activity in cancer cells through downregulation of IKK activity

Cited by 43 publications

References 37 publications

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Lobolide, a diterpene, blockades the NF-κB pathway and p38 and ERK MAPK activity in macrophages in vitro

The Small Molecule GMX1778 Is a Potent Inhibitor of NAD⁺ Biosynthesis: Strategy for Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors

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Anticancer agent CHS 828 suppresses nuclear factor‐κB activity in cancer cells through downregulation of IKK activity

Cited by 43 publications

References 37 publications

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Lobolide, a diterpene, blockades the NF-κB pathway and p38 and ERK MAPK activity in macrophages in vitro

The Small Molecule GMX1778 Is a Potent Inhibitor of NAD+ Biosynthesis: Strategy for Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors

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The Small Molecule GMX1778 Is a Potent Inhibitor of NAD⁺ Biosynthesis: Strategy for Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors