Saracatinib inhibits TGF-β–induced phenotypic changes in human lung fibroblasts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE178518 | GEO | 2022/08/30
REPOSITORIES: GEO
Similar Datasets
Project description:Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Using an in-silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor, originally developed for oncological indications.We investigated the anti-fibrotic efficacy of saracatinib in two in vivo modeles (bleomycin and recombinant adenovirus transforming growth factor-beta (Ad-TGF-β) murine models of pulmonary fibrosis).
2022-08-30 | GSE178457 | GEO
Project description:Biliary tract carcinoma (BTC) has a poor prognosis due to limited treatment options. There is therefore urgent need to identify new targets and to design innovative therapeutic approaches. Among potential candidate molecules, we evaluated the non-receptor tyrosine kinase Src, observing promising antitumor effects of its small molecule inhibitor Saracatinib in BTC preclinical models. The presence of an active Src protein was investigated by immunohistochemistry in 19 surgical samples from BTC patients. Upon Saracatinib treatment, the phosphorylation of Src and of its downstream transducers was evaluated in the BTC cell lines TFK-1, EGI-1, HuH28 and TGBC1-TKB. The effect of Saracatinib on proliferation and migration was analyzed in these same cell lines, and its antitumor activity was essayed in EGI-1 mouse xenografts. Saracatinib-modulated transcriptome was profiled in EGI-1 cells and in tumor samples of the xenograft model. Src was activated in about 80% of the human BTC samples. In cultured BTC cell lines, low-dose Saracatinib counteracted the activation of Src and of its downstream effectors, increased the fraction of cells in G0/G1 phase, and inhibited cell migration. At high concentrations (median dose from 2.26 to 6.99 µM), Saracatinib was also capable of inhibiting BTC cell proliferation. In vivo, Saracatinib treatment resulted in delayed tumor growth, associated with an impaired vascular network. We here provide a demonstration that the targeted inhibition of Src kinase by Saracatinib is of therapeutic benefit in preclinical models of BTC. We propose our results as a basis for the design of Saracatinib-based clinical applications. EGI-1 cell line treated with Saracatinib at the dose of 10 µM vs EGI-1 cell line untreated; EGI-1 xenograft treated with Saracatinib at the dose of 25 mg/Kg/die vs EGI-1 xenograft untreated Transcriptional alteration mediated by Saracatinib in vitro and in vivo
2012-08-02 | E-GEOD-36622 | biostudies-arrayexpress
Project description:Biliary tract carcinoma (BTC) has a poor prognosis due to limited treatment options. There is therefore urgent need to identify new targets and to design innovative therapeutic approaches. Among potential candidate molecules, we evaluated the non-receptor tyrosine kinase Src, observing promising antitumor effects of its small molecule inhibitor Saracatinib in BTC preclinical models. The presence of an active Src protein was investigated by immunohistochemistry in 19 surgical samples from BTC patients. Upon Saracatinib treatment, the phosphorylation of Src and of its downstream transducers was evaluated in the BTC cell lines TFK-1, EGI-1, HuH28 and TGBC1-TKB. The effect of Saracatinib on proliferation and migration was analyzed in these same cell lines, and its antitumor activity was essayed in EGI-1 mouse xenografts. Saracatinib-modulated transcriptome was profiled in EGI-1 cells and in tumor samples of the xenograft model. Src was activated in about 80% of the human BTC samples. In cultured BTC cell lines, low-dose Saracatinib counteracted the activation of Src and of its downstream effectors, increased the fraction of cells in G0/G1 phase, and inhibited cell migration. At high concentrations (median dose from 2.26 to 6.99 µM), Saracatinib was also capable of inhibiting BTC cell proliferation. In vivo, Saracatinib treatment resulted in delayed tumor growth, associated with an impaired vascular network. We here provide a demonstration that the targeted inhibition of Src kinase by Saracatinib is of therapeutic benefit in preclinical models of BTC. We propose our results as a basis for the design of Saracatinib-based clinical applications.
2012-08-03 | GSE36622 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease with a poor prognosis. Fibroblasts and myofibroblasts are the key cells in the fibrotic process. Pirfenidone was approved as an anti-fibrotic drug for IPF treatment as it is able to slow disease progression. The mechanisms by which the drug acts on fibroblasts are not clear. Therefore, this study aims to examine the effects of pirfenidone on the human lung fibroblast (HLF) transcriptome in vitro.
2023-05-12 | GSE226249 | GEO
Project description:Idiopathic Pulmonary Fibrosis (IPF) is a progressive chronic lung disease characterized by excess deposition of extracellular matrix (ECM) proteins in the lung. TGFα is a is a ligand for the epidermal growth factor receptor, and found elevated in several fibrotic lung diseases including IPF. Notably, lung-specific overexpression of TGFα alone in adult mice can cause progressive and extensive adventitial and subpleural fibrosis similar to IPF. Pirfenidone, an FDA approved drug has been shown to improve the decline in lung function in IPF patients. However, the mechanism of action of pirfenidone largely unknown. In the current study, we investigated the effects of pirfenidone using a mouse model of TGFα-induced pulmonary fibrosis and fibroblasts isolated from IPF lungs. Total lung transcriptome analysis suggest a significant overlap in dysregulated gene transcripts between TGFα model and IPF. In vivo studies demonstrate a significant improvement in lung function with pirfenidone therapy compared to vehicle-treated TGFα mice on Dox for six wks. However, pirfenidone treatment did not affect fibroproliferation, myofibroblast transformation, and ECM deposition during TGFα-induced pulmonary fibrosis. In summary, pirfenidone treatment improved lung function but had a limited or no effect on the expression of collagen, ECM genes, fibroproliferation and migration of lung-resident fibroblasts.
2022-06-01 | GSE199034 | GEO
Project description:Background:Oxaliplatin-resistant hepatocellular carcinoma (HCC) is associated with increased insulin-like growth factor 1 (IGF1) paracrine signaling, and the IGF1 receptor can be downregulated by inhibition of Src kinases. Therefore, we sought to determine whether Src inhibition and oxaliplatin treatment exerted synergistic effects on HCC cell lines. Methods: The antitumor effects of combined treatment with saracatinib and oxaliplatin on proliferation were evaluated in HCC cells as well as in saracatinib- and oxaliplatin-resistant HCC cell lines using cell viability assays, plate colony formation assays, and cell cycle distribution detection. RNA sequencing was used to explore the resistance mechanism, and the effects on ABCG1 and Wnt signaling in oxaliplatin resistance were confirmed. Results: Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. Furthermore, treatment with saracatinib caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding the ATP-binding cassette transporter G1 ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in the HCC cell lines. Conclusions: These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the upregulation of ABCG1 and activation of Wnt signaling pathway by saracatinib.
2019-03-30 | GSE129071 | GEO
Project description:We sought to detect predictive markers related to a Src kinase inhibitor (saracatinib) sensitivity in ovarian cancer. Cell proliferation assays assigned 18 ovarian cancer cell lines to sensitive or resistant to this drug. Using baseline gene expression data from these 18 cell lines, we sought to identify differentially expressed genes correlated with saracatinib sensitivity. We also used SNP array data from 7 cell lines to detect differentically affected genomic locations.
2017-03-05 | GSE55628 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a life-threatening and progressive scarring disease of the lung. Loss of alveolar epithelial cells, inflammation, activation of fibroblasts, appearance of myofibroblasts and excessive deposition of extracellular matrix (ECM) are central features of IPF pathogenesis, ultimately resulting in changes in tissue architecture and lung dysfunction. The two currently approved therapies, pirfenidone (Esbriet®) and nintedanib (Ofev®), significantly slow the rate of disease progression, but they do not halt or reverse tissue remodeling. Therefore, disease modifying strategies that influence (myo)fibroblast activity and ECM deposition could lead to promising new treatments. Here we demonstrate potent and effective in vitro antifibrotic properties of the selective prostacyclin (IP) receptor agonist, ACT-333679, on TGFβ1-stimulated primary human lung fibroblasts from non-diseased and IPF donors. We demonstrate that ACT-333679 inhibited fibrotic processes through elevation of cAMP, inhibition of YAP/TAZ signaling and subsequent suppression of YAP/TAZ-induced gene transcription. Our results describe attenuation of YAP/TAZ signaling through IP receptor activation as a novel mechanism that suppresses pro-fibrotic (myo)fibroblast activity and we offer a rationale to further explore the potential of IP receptor agonists for the treatment of IPF .
2019-01-24 | GSE109585 | GEO
Project description:Two antifibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells are immunocompetent cells that can predispose to those within the lungs and orchestrate cell-cell interactions associated with IPF pathogenesis. We employed RNA sequencing to examine the transcriptome signature in bulk peripheral blood mononuclear cells of patients with IPF and the effects of antifibrotic drugs on these signatures. Differentially expressed genes (DEGs) were analyzed in patients with IPF and healthy controls, before and after antifibrotic treatment. Enrichment analysis suggested that fatty acid elongation interferes with profibrotic TGF-β/ signaling and production of oxidative stress since treatment with NTD upregulated the elongation enzymes ELOVL6 and ELOVL7. Treatment with PFD downregulated COL1A1 which produces wound-healing collagens, as activated monocyte-derived macrophages during tissue damage participate in the production of collagen, type I, and alpha 1. Plasminogen activator inhibitor-1 (PAI-1) regulates wound healing by inhibiting plasmin-mediated matrix metalloproteinases activation, and inhibition of PAI-1 activity attenuates lung fibrosis. DEGs analysis suggested that both PFD and NTD upregulated SERPINE1 which in turn regulates PAI-1 activity. This study detected different DEGs as a result of PFD and NTD treatments, suggesting different mechanistic roles for the two antifibrotic drugs.
2024-03-28 | GSE248485 | GEO
Project description:Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β1 exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, administration of Ogg1-targetting siRNA, mitigated bleomycin-induced pulmonary fibrosis in mice, thereby highlighting OGG1 as a tractable target in lung fibrosis. The novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation, with both increased in fibrotic murine and IPF patient lung tissue. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF. This DIA-MS dataset entails the raw data and peptide-centric DIA-NN search results of both, lung tissue and bronchoalveolar lavage fluid of n=5 mice profiled across the treatment groups bleomycin combined with TH (BTH), dexamethasone (DEX), TH alone (TH) and vehicle control (V) relative to bleomycin alone (B) as control. Different animals within protein groups were considered biological replicates of the respective treatment condition.
2023-02-06 | PXD029625 | Pride