Treatment Effects of the Second-Generation Tyrosine Kinase Inhibitor Dasatinib on Autoimmune Arthritis

Guo, Kai; Bu, Xin; Yang, Ching Fen; Cao, Xiaohong; Bian, Hui; Zhu, Qing; Zhu, Jinyu; Zhang, Dawei

doi:10.3389/fimmu.2018.03133

Cited by 29 publications

(32 citation statements)

References 57 publications

(62 reference statements)

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“…These ndings are in line with previous reports supporting that dasatinib demonstrates convergent bone anabolic (29) and reduced bone resorption effects (29), osteoclast inhibitory functions (51), enhancement of chondrogenesis (52) as well as enhanced bone preservation in metastatic cancers (53,54). Moreover a similar effect has been recently reported for the effect of dasatinib in the CIA model of arthritis (41). These ndings, together with our data, support that dasatinib has the potential to moderate bone-related pathologies in arthritis.…”

Section: Discussionsupporting

confidence: 93%

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Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Ntari¹,

Nikolaou

Kranidioti³

et al. 2020

Preprint

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Background Medications for Rheumatoid Arthritis (RA) have emerged in the last two decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients. Methods We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy. Results Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-depended manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy. Conclusion Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of this combination therapy may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.

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Section: Discussionsupporting

confidence: 93%

“…These data suggest that these two TKIs may have the potential to interrupt the persistent pathogenic crosstalk between synovial stromal cells and immune cells thus slowing down in the progression of the arthritis pathology. Similar ability of dasatinib to control the arthritogenic phenotype of human RASFs has been previously reported (41).…”

Section: Discussionsupporting

confidence: 83%

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Ntari¹,

Nikolaou

Kranidioti³

et al. 2020

Preprint

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“…Dasatinib has been proposed as an agent for fibrotic diseases, based on its inhibition of TGFbeta-induced myofibroblast differentiation through SRC-mediated signaling in vitro ( 101 ). Dasatinib blocked production of pro-inflammatory cytokines in a model of autoimmune arthritis, including IL-1, TNF-alpha, and IL-6, and stimulated production of the anti-inflammatory cytokine IL-10 ( 102 ) ( 103 ), and caused macrophages to change to an anti-inflammatory phenotype marked by high IL-10 production and suppression of levels of pro-inflammatory cytokines (IL-6, TNF-alpha) ( 104 ). Preclinical studies with the SRC/ABL inhibitor, saracatinib, which has orphan drug status for idiopathic pulmonary fibrosis, showed that it decreases collagen deposition and fibroblast activity, which are characteristic of lung fibrosis ( 105 ).…”

Section: Abl Pdgfr and Src Inhibitorsmentioning

confidence: 99%

Repurposing of Kinase Inhibitors for Treatment of COVID-19

et al. 2020

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The outbreak of COVID-19, the pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an intense search for treatments by the scientific community. In the absence of a vaccine, the goal is to target the viral life cycle and alleviate the lung-damaging symptoms of infection, which can be lifethreatening. There are numerous protein kinases associated with these processes that can be inhibited by FDA-approved drugs, the repurposing of which presents an alluring option as they have been thoroughly vetted for safety and are more readily available for treatment of patients and testing in clinical trials. Here, we characterize more than 30 approved kinase inhibitors in terms of their antiviral potential, due to their measured potency against key kinases required for viral entry, metabolism, or reproduction. We also highlight inhibitors with potential to reverse pulmonary insufficiency because of their anti-inflammatory activity, cytokine suppression, or antifibrotic activity. Certain agents are projected to be dualpurpose drugs in terms of antiviral activity and alleviation of disease symptoms, however drug combination is also an option for inhibitors with optimal pharmacokinetic properties that allow safe and efficacious co-administration with other drugs, such as antiviral agents, IL-6 blocking agents, or other kinase inhibitors.

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“…Rheumatoid arthritis (RA) is an autoimmune disease that includes multiple disease subsets defined by the several inflammatory cascades that result in a final shared pathway where persistent synovial inflammation leads to damage to articular cartilage and underlying bone [1–4]. The etiology of RA continues to be investigated [5], but genetic factors are found in 50% of patients who develop RA [6], and more than 30 genetic regions have been linked to RA [7,8]. RA currently affects 0.1–0.5% of adults and is approximately three times more common in women and increases with age, with the highest incidence in women who are more than 65 years [9,10].…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Synovial Inflammation in Rheumatoid Arthritis

Xiong

Liu

et al. 2019

Med Sci Monit

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Background Rheumatoid arthritis (RA) has a high prevalence in the elderly population. The genes and pathways in the inflamed synovium in patients with RA are poorly understood. This study aimed to identify differentially expressed genes (DEGs) linked to the progression of synovial inflammation in RA using bioinformatics analysis. Material/Methods Gene expression profiles of datasets GSE55235 and GSE55457 were acquired from the Gene Expression Omnibus (GEO) database. DEGs were identified using Morpheus software, and co-expressed DEGs were identified with Venn diagrams. Protein-protein interaction (PPI) networks were assembled with Cytoscape software and separated into subnetworks using the Molecular Complex Detection (MCODE) algorithm. The functions of the top module were assessed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. Results DEGs that were upregulated were significantly enhanced in protein binding, the cell cytosol, organization of the extracellular matrix (ECM), regulation of RNA transcription, and cell adhesion. DEGs that were downregulated were associated with control of the immune response, B-cell and T-cell receptor signaling pathway regulation. KEGG pathway analysis showed that upregulated DEGs enhanced pathways associated with the cell adherens junction, osteoclast differentiation, and hereditary cardiomyopathies. Downregulated DEGs were enriched in primary immunodeficiency, cell adhesion molecules (CAMs), cytokine-cytokine receptor interaction, and hematopoietic cell lineages. Conclusions The findings from this bioinformatics network analysis study identified molecular mechanisms and the key hub genes that may contribute to synovial inflammation in patients with RA.

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Treatment Effects of the Second-Generation Tyrosine Kinase Inhibitor Dasatinib on Autoimmune Arthritis

Cited by 29 publications

References 57 publications

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Repurposing of Kinase Inhibitors for Treatment of COVID-19

Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Synovial Inflammation in Rheumatoid Arthritis

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