First Non-ATP Competitive Glycogen Synthase Kinase 3 β (GSK-3β) Inhibitors:  Thiadiazolidinones (TDZD) as Potential Drugs for the Treatment of Alzheimer's Disease

Martı́nez, Ana; Alonso, Mercedes; Castro, Ana; Pérez, Concepción; Moreno, Francisco J.

doi:10.1021/jm011020u

Cited by 432 publications

(364 citation statements)

References 34 publications

(72 reference statements)

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“…SB-216763 inhibits GSK-3 in vitro with an IC 50 value of less than 100 nM with no significant inhibition of 24 other protein kinases (Coghlan et al, 2000). TDZD8, a potent inhibitor of GSK-3 (IC 50 ¼ 2 mM), did not inhibit protein kinases A or C, CK-2 or CDK1/cyclin B kinases at 4100 mM (Martinez et al, 2002). Docetaxel was from Sigma-Aldrich Japan.…”

Section: Cell Culture and Reagentsmentioning

confidence: 99%

“…To determine whether active GSK-3 is essential for RCC cell survival and proliferation, first we tested the effect of three chemically distinct small molecule inhibitors of GSK-3: AR-A014418 (ATPcompetitive) (Bhat et al, 2003), SB-216763 (ATP-competitive) (Coghlan et al, 2000), and TDZD8 (non-ATP-competitive) (Martinez et al, 2002) in ACHN renal cancer cells ( Figure 3A).…”

Section: Gsk-3b Is Expressed and Active In Human Renal Cancer Cellsmentioning

confidence: 99%

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Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma

et al. 2009

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BACKGROUND: Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3b positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF-kB)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3b and to assess the anti-cancer effect of GSK-3b inhibition in RCC. METHODS: Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3b in human RCCs. We used small molecule inhibitor, RNA interference, western blotting, quantitative RT -PCR, BrDU incorporation and MTS assays to study the effect of GSK-3b inactivation on renal cancer cell proliferation and survival. RESULTS: We detected aberrant nuclear accumulation of GSK-3b in RCC cell lines and in 68 out of 74 (91.89%) human RCCs. We found that pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of renal cancer cells. We observed that inhibition of GSK-3 results in decreased expression of NF-kB target genes Bcl-2 and XIAP and a subsequent increase in renal cancer cell apoptosis. Moreover, we show that GSK-3 inhibitor and Docetaxel synergistically suppress proliferation and survival of renal cancer cells. CONCLUSIONS: Our results show nuclear accumulation of GSK-3b as a new marker of human RCC, identify that GSK-3 positively regulates RCC cell survival and proliferation and suggest inhibition of GSK-3 as a new promising approach in the treatment of human renal cancer.

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Section: Cell Culture and Reagentsmentioning

confidence: 99%

Section: Gsk-3b Is Expressed and Active In Human Renal Cancer Cellsmentioning

confidence: 99%

Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma

et al. 2009

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“…6). TDZD-8 is a highly selective, non-ATP inhibitor of GSK-3␤ that phosphorylates and inactivates kinase activity (39,40). Treatment of NK cells with GSK-3␤ inhibitor should lead to dissociation of ␤-catenin from GSK-3, its translocation to the nucleus, and increased cytotoxicity by NK cells.…”

Section: Phosphorylation and Inactivation Of Gsk Up-regulate Nk Cellmentioning

confidence: 99%

Role for Glycogen Synthase Kinase-3 in NK Cell Cytotoxicity and X-Linked Lymphoproliferative Disease

Aoukaty

Tan

2005

The Journal of Immunology

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NK cells from individuals with X-linked lymphoproliferative (XLP) disease exhibit functional defects when stimulated through the NK receptor, 2B4 (CD244). These defects are likely a consequence of aberrant intracellular signaling initiated by mutations of the adaptor molecule SLAM-associated protein. In this report, we show that NK cells from individuals with XLP but not healthy individuals fail to phosphorylate and thereby inactivate glycogen synthase kinase-3 (GSK-3) following 2B4 stimulation. Lack of GSK-3 phosphorylation prevented the accumulation of the transcriptional coactivator β-catenin in the cytoplasm and its subsequent translocation to the nucleus. Potential signaling pathways leading from 2B4 stimulation to GSK-3 phosphorylation were also investigated. Ligation of 2B4 resulted in the phosphorylation of the guanine nucleotide exchange factor, Vav-1, and subsequent activation of the GTP-binding protein Rac-1 (but not Ras) and the serine-threonine kinase Raf-1 in healthy but not XLP-derived NK cells. In addition, the activity of MEK-2 (but not MEK-1) was up-regulated, and Erk1/2 was phosphorylated in normal NK cells but not those from an individual with XLP suggesting that these proteins relay SLAM-associated protein-dependent signals from 2B4. Finally, inactivation of GSK-3 using a specific inhibitor of GSK-3β increased the cytotoxicity and cytokine secretion of both healthy and XLP NK cells. These data indicate that the signaling of 2B4 in NK cells is mediated by GSK-3 and β-catenin, possibly through a signal transduction pathway that involves Vav-1, Rac-1, Raf-1, MEK-2, and Erk1/2 and that this pathway is aberrant in individuals with XLP.

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“…The inhibition mechanism of FK506 and cyclosporine A to calcineurin is remarkable, because both compounds are bound by their respective binding proteins (immunophilins), named FKBP12 and cyclophilin A, and their complexes inhibit calcineurin, leading to suppressed T cell activation [11,12]. In addition, we have already found that the Ca 2ϩ channel blocker diltiazem [13], the inhibitor of HSP90 called radicicol [5], and the GSK-3b inhibitor GSK-3b inhibitor I [14] also inhibit each molecular target in the Ca 2ϩ -signal transduction of S. cerevisiae and showed the growth zone only and/or the growth zone with an inhibition zone on the plate (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

New Eremophilane Sesquiterpenoid Compounds, Eremoxylarins A and B Directly Inhibit Calcineurin in a Manner Independent of Immunophilin

et al. 2008

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In the course of our screening program for a new Ca 2ϩ -signal transduction inhibitor using the hypersensitive mutant strain of Saccharomyces cerevisiae (zds1D erg3D pdr1D pdr3D ), new eremophilane sesquiterpenoid compounds eremoxylarins A and B were found to restore the growth inhibition caused by the hyperactivated Ca 2ϩ -signal. These compounds showed lethal activity against the mpk1D strain, specifically, compared to the cnb1D strain, and ion-sensitive activity against the wild-type strain in the presence of LiCl, indicating that their molecular target might be the calcineurin pathway. They inhibited calcineurin directly without immunophilins at IC 50 ϭ2.7 and 1.4 m M with competitive inhibition in vitro. The eremophilane sesquiterpenoid structure in eremoxylarins could be a good leading compound for immunosuppressants and anti-allergy drugs.

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First Non-ATP Competitive Glycogen Synthase Kinase 3 β (GSK-3β) Inhibitors: Thiadiazolidinones (TDZD) as Potential Drugs for the Treatment of Alzheimer's Disease

Cited by 432 publications

References 34 publications

Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma

Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma

Role for Glycogen Synthase Kinase-3 in NK Cell Cytotoxicity and X-Linked Lymphoproliferative Disease

New Eremophilane Sesquiterpenoid Compounds, Eremoxylarins A and B Directly Inhibit Calcineurin in a Manner Independent of Immunophilin

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