Inhibitory effects of ZSTK474, a phosphatidylinositol 3-kinase inhibitor, on adjuvant-induced arthritis in rats

Haruta, Kazuhiko; Mori, Shigeyuki; Tamura, Naoto; Sasaki, Asako; Nagamine, Masakazu; Yaguchi, Shin‐ichi; Kamachi, Fumitaka; Enami, Jumpei; Kobayashi, Shigeto; Yamori, Takao; Takasaki, Yoshinari

doi:10.1007/s00011-012-0444-8

Cited by 15 publications

(13 citation statements)

References 41 publications

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“…The expression of phosphorylated Akt is upregulated in RA synovium (29) and is attributed to apoptosis resistance in RA-derived fibroblasts (30). As a therapeutic approach for arthritis, the pan-class I PI3K inhibitor ZSTK474 was reported to suppress articular inflammation in vivo (18,19). Therefore, we selected ZSTK474 for the second screening of invasion/migration inhibitor candidates, as it could have effects on SFs.…”

Section: Discussionmentioning

confidence: 99%

“…ZSTK474 is a synthesized s-triazine derivative that strongly inhibits the growth of cancer cells grafted into mice without organ toxicity (16) and was subsequently identified as a novel pan-class I PI3K inhibitor (17). As several reports are available on the therapeutic effectiveness of ZSTK474 in RA animal models (18,19), ZSTK474 was included in the second screening instead of wortmannin and LY-294002.…”

Section: Candidate Inhibitors Differentially Affect Sfs Invasion In Tmentioning

confidence: 99%

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Screening of a Panel of Low Molecular Weight Compounds That Inhibit Synovial Fibroblast Invasion in Rheumatoid Arthritis

Sugiura

Kamino

Nariai

et al. 2020

The Journal of Immunology

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Increased invasion of synovial fibroblasts and their involvement in cartilage damage are characteristic phenotypes of rheumatoid arthritis (RA). To identify low molecular weight compounds that suppress synovial fibroblast invasion, a panel of inhibitors (n = 330) was initially screened using a real-time cell analysis system for human synovial fibroblasts that were enzymatically isolated from surgical samples of RA patients. To evaluate the effects of the inhibitors identified in the screen, synovial fibroblast migration was measured using a wound-healing assay, and phosphorylation of intracellular signaling molecules was determined by immunoblots. Several candidate inhibitors were identified in the screen, including inhibitors against platelet-derived growth factor receptor (PDGFR), Akt, PI3K, and glycogen kinase synthetase 3 (GSK-3). These inhibitors strongly suppressed synovial fibroblast migration after 72 h and downregulated phosphorylation of Akt (Ser473) at 48 h. When the inhibitors were removed from the culture conditions, both migration and phosphorylated Akt (Ser473) levels were restored. Furthermore, all the categories of inhibitors except for PDGFR inhibitor IV decreased cell proliferation as well as IL-6 production in synovial fibroblasts. Interestingly, GSK-3 inhibitors increased anti-inflammatory cytokine IL-10 production but suppressed IL-23 production from LPS-primed macrophages obtained from healthy donors. In conclusion, blocking PDGFR, PI3K, or GSK-3 could have therapeutic value as an RA treatment that targets the invasion/migration of synovial fibroblasts.

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Section: Discussionmentioning

confidence: 99%

Section: Candidate Inhibitors Differentially Affect Sfs Invasion In Tmentioning

confidence: 99%

Screening of a Panel of Low Molecular Weight Compounds That Inhibit Synovial Fibroblast Invasion in Rheumatoid Arthritis

Sugiura

Kamino

Nariai

et al. 2020

The Journal of Immunology

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“…Inhibitors of two other kinases that indirectly activate the JNK pathway, PI3K isoforms (especially PI3Kδ) 44,75 and tyrosine-protein kinase SYK 76 (which is also expressed at high levels in several immune cell types), are also considered promising strategies to tame FLS hyper activation in RA. Small-molecule inhibitors of SYK have already demonstrated efficacy in a phase II trial in 457 patients with active RA and an inadequate response to methotrexate.…”

Section: Targeting Fls In Ramentioning

confidence: 99%

Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors

Bottini

Firestein²

2012

Nat Rev Rheumatol

724

704

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Rheumatoid arthritis (RA) is characterized by hyperplastic synovial pannus tissue, which mediates destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS) are a key component of this invasive synovium and have a major role in the initiation and perpetuation of destructive joint inflammation. The pathogenic potential of FLS in RA stems from their ability to express immunomodulating cytokines and mediators as well as a wide array of adhesion molecule and matrix-modelling enzymes. FLS can be viewed as ‘passive responders’ to the immunoreactive process in RA, their activated phenotype reflecting the proinflammatory milieu. However, FLS from patients with RA also display unique aggressive features that are autonomous and vertically transmitted, and these cells can behave as primary promoters of inflammation. The molecular bases of this ‘imprinted aggressor’ phenotype are being clarified through genetic and epigenetic studies. The dual behaviour of FLS in RA suggests that FLS-directed therapies could become a complementary approach to immune-directed therapies in this disease. Pathophysiological characteristics of FLS in RA, as well as progress in targeting these cells, are reviewed in this manuscript.

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“…Since this compound has been tested as an anticancer drug in phase I clinical trials [7–10], some basic knowledge has been gained about its effects in humans. Previous research has demonstrated, for example, that ZSTK474 has anti-inflammatory properties which could protect mice from collagen-induced arthritis and multiple sclerosis, both of which are autoimmune inflammatory diseases [11–13]. Since those findings indicate that ZSTK474 has anti-inflammatory and immunoregulatory potential, it is reasonable to hypothesize that ZSTK474 may improve the prognosis of patients with cerebral ischemia/reperfusion injury by inhibiting the inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Class I PI3K inhibitor ZSTK474 mediates a shift in microglial/macrophage phenotype and inhibits inflammatory response in mice with cerebral ischemia/reperfusion injury

Wang

et al. 2016

J Neuroinflammation

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BackgroundMicroglia/macrophages play a critical role in the inflammatory and immune processes of cerebral ischemia/reperfusion injury. Since microglia/macrophages can reversibly shift their phenotype toward either a “detrimental” or a “restorative” state in the injured central nervous system (CNS), compounds mediate that shift which could inhibit inflammation and restore the ability to alleviate cerebral ischemia/reperfusion injury would have therapeutic potential.MethodsTransient middle cerebral artery occlusion was induced in male C57BL/6 mice. Mice were randomly separated into a sham-operated group, a control group, and a ZSTK474-treated group. We investigated the effect of ZSTK474 by assessing neurological deficits, infarct volume, and histopathological changes. We then determined the potential mechanism by immunofluorescent staining, quantitative real-time polymerase chain reaction (PCR), and Western blot analysis. The Tukey’s test or Mann–Whitney U test was used to compare differences among the groups.ResultsZSTK474 alleviated neurological deficits and reduced infarct volume in the cerebral ischemia/reperfusion injury model. Presumably, ZSTK474 shifted the phenotype of microglia/macrophages to a restorative state, since this treatment decreased the secretion of pro-inflammatory factors and advanced the secretion of anti-inflammatory factors. These neuroprotective properties of ZSTK474 may be mediated by the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway.ConclusionsZSTK474 can mediate a shift in microglia/macrophage phenotype and inhibit the inflammatory response in cerebral ischemia reperfusion injury of mice. These effects appeared to ensue via the PI3K/AKT/mTORC1 pathway. Therefore, ZSTK474 may represent a therapeutic intervention with potential for circumventing the catastrophic aftermath of ischemic stroke.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0660-1) contains supplementary material, which is available to authorized users.

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Inhibitory effects of ZSTK474, a phosphatidylinositol 3-kinase inhibitor, on adjuvant-induced arthritis in rats

Abstract: ZSTK474 demonstrated prophylactic efficacy in a rat model of rheumatoid arthritis (RA) through inhibition of T cell and FLS functions. It was suggested that the inhibitors of PI3K have therapeutic potential for RA.

Cited by 15 publications

References 41 publications

Screening of a Panel of Low Molecular Weight Compounds That Inhibit Synovial Fibroblast Invasion in Rheumatoid Arthritis

Screening of a Panel of Low Molecular Weight Compounds That Inhibit Synovial Fibroblast Invasion in Rheumatoid Arthritis

Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors

Class I PI3K inhibitor ZSTK474 mediates a shift in microglial/macrophage phenotype and inhibits inflammatory response in mice with cerebral ischemia/reperfusion injury

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