The Novel Orally Active Proteasome Inhibitor K-7174 Exerts Anti-myeloma Activity in Vitro and in Vivo by Down-regulating the Expression of Class I Histone Deacetylases

Kikuchi, Jiro; Yamada, Satoshi; Koyama, Daisuke; Wada, Taeko; Nobuyoshi, Masaharu; Izumi, Tohru; Akutsu, Miyuki; Kano, Yasuhiko; Furukawa, Yusuke

doi:10.1074/jbc.m113.480574

Cited by 25 publications

(22 citation statements)

References 44 publications

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“…Active caspase 8 blocks necrosis by proteolytically inactivating RIPK1 and RIPK3 (19, 36, 37). Thus we next inhibited caspase 8 activation in H37Ra-infected Mφ using the selective caspase 8 inhibitor z-IETD-FMK and then measured the levels of mitochondria-associated RIPK3.…”

Section: Resultsmentioning

confidence: 99%

Bcl-xL mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages

et al. 2017

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Virulent Mycobacterium tuberculosis (Mtb) triggers necrosis in host Mφ, which is essential for successful pathogenesis. Here we demonstrate that necrosis of Mtb-infected Mφ is dependent on the action of the cytosolic kinase Receptor Interacting Protein 3 (RIPK3) and the mitochondrial Bcl-2 family member protein B-cell lymphoma - extra large (Bcl-xL). RIPK3-deficient Mφ are able to better control bacterial growth in vitro and in vivo. Cytosolic RIPK3 translocates to the mitochondria where it promotes necrosis and blocks caspase 8-activation and apoptosis via Bcl-xL. Furthermore, necrosis is associated with stabilization of hexokinase II on the mitochondria as well as cyclophilin D-dependent mitochondrial permeability transition (MPT). These events up-regulate the level of reactive oxygen species (ROS) to induce necrosis. Thus, in Mtb-infected Mφ mitochondria are an essential platform for induction of necrosis by activating RIPK3 function and preventing caspase 8 - activation.

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Section: Resultsmentioning

confidence: 99%

Bcl-xL mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages

et al. 2017

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“…Cells were suspended in 100 μl of RPMI 1640 medium before injection. RPMI8226-Luc cells were inoculated subcutaneously in the right and left thighs of NOD/SCID mice (Charles River Laboratories) (47). MOPC315.BM.Luc cells were injected intravenously into BALB/c mice (Charles River Laboratories) (35).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

Kikuchi

Koyama

Wada

et al. 2015

Journal of Clinical Investigation

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“…Prior to this analysis, we reassessed a known GATA inhibitor, K-7174 (29,30). While K-7174 has been reported to inhibit the activity of GATA factors in multiple cell types, a recent study suggested that K-7174 has potential cytotoxicity due to proteasome-inhibitory activity (31). Considering this disadvantage of K-7174, we decided to screen and identify novel GATA factor inhibitors by means of high-throughput screening (HTS) of a chemical compound library.…”

Section: Resultsmentioning

confidence: 99%

Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury

Moriguchi

Kaneko

et al. 2017

Molecular and Cellular Biology

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Acute kidney injury (AKI) is a leading cause of chronic kidney disease. Proximal tubules are considered to be the primary origin of pathogenic inflammatory cytokines in AKI. However, it remains unclear whether other cell types, including collecting duct (CD) cells, participate in inflammatory processes. The transcription factor GATA2 is specifically expressed in CD cells and maintains their cellular identity. To explore the pathophysiological function of GATA2 in AKI, we generated renal tubular cell-specific deletion (G2CKO) mice and examined their susceptibility to ischemia reperfusion injury (IRI). Notably, G2CKO mice exhibited less severe kidney damage, with reduced granulomacrophagic infiltration upon IRI. Transcriptome analysis revealed that a series of inflammatory cytokine genes were downregulated in GATA2-deficient CD cells, suggesting that GATA2 induces inflammatory cytokine expression in diseased kidney CD cells. Through high-throughput chemical library screening, we identified a potent GATA inhibitor. The chemical reduces cytokine production in CD cells and protects the mouse kidney from IRI. These results revealed a novel pathological mechanism of renal IRI, namely, that CD cells produce inflammatory cytokines and promote IRI progression. In injured kidney CD cells, GATA2 exerts a proinflammatory function by upregulating inflammatory cytokine gene expression. GATA2 can therefore be considered a therapeutic target for AKI.

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The Novel Orally Active Proteasome Inhibitor K-7174 Exerts Anti-myeloma Activity in Vitro and in Vivo by Down-regulating the Expression of Class I Histone Deacetylases

Cited by 25 publications

References 44 publications

Bcl-xL mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages

Bcl-xL mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages

Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury

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