Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis

Daniels, Craig; Wilkes, Mark C.; Edens, Maryanne; Kottom, Ted J.; Murphy, Stephen J.; Limper, Andrew H.; Leof, Edward B.

doi:10.1172/jci19603

Cited by 264 publications

(245 citation statements)

References 49 publications

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“…Interest in use of imatinib mesylate in SSc lies in its ability to interfere with the tyrosine kinases downstream of the receptors for transforming growth factor beta and platelet-derived growth factor, which are considered key signaling molecules in the pathogenesis of SSc fibrosis [8,9]. …”

Section: Introductionmentioning

confidence: 99%

Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study

et al. 2014

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IntroductionPulmonary involvement represents a major cause of death of systemic sclerosis (SSc) patients. Recent data suggest that tyrosine kinase inhibitors, such as imatinib, may be a therapeutic option for SSc patients. However, preliminary published clinical trials were inconclusive about imatinib efficacy and showed side effects. The purpose of this study was to verify efficacy and tolerability of low-dose imatinib on interstitial lung disease in a cohort of SSc patients unresponsive to cyclophosphamide therapy.MethodsThirty consecutive SSc patients with active pulmonary involvement, unresponsive to cyclophosphamide, were treated with imatinib 200 mg/day for 6 months followed by a 6-month follow-up. A “good response” was defined as an increase of forced vital capacity (FVC) by more of 15% and/or increase of diffusing capacity of carbon monoxide (DLCO) >15% and PaO2 > 90% of initial value and high-resolution computed tomography (HRCT)-scan pattern unchanged or improved.ResultsTwenty-six patients completed the study. Three patients died and one patient was lost to follow-up. Four patients (15.32%) had a good response, 7 worsened and 15 had a stabilized lung disease. Overall, 19 (73.07%) patients had an improved or stabilized lung disease. After a 6-month follow-up, 12 (54.5%) of the 22 patients showed an improved or stabilized lung disease.ConclusionsLung function was stabilized in a large proportion of patients unresponsive to cyclophosphamide therapy and a beneficial outcome emerged from the analysis of HRCT lung scans. There was no significant improvement of skin involvement, and the low dose was well tolerated. These data provide useful suggestions to design future randomized clinical trials for SSc therapeutics.Trial registrationClinicalTrials.gov NCT00573326. Registered 13 December 2007.

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Section: Introductionmentioning

confidence: 99%

Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study

et al. 2014

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“…We and others demonstrated recently that imatinib mesylate (Gleevec®/Glivec®, Novartis, Basel, Switzerland) exerts potent anti-fibrotic effects [2, 3]. Imatinib is a small molecule inhibitor that binds to the ATP-binding pocket of abelson kinase (c-abl) and blocks efficiently its tyrosine kinase activity.…”

Section: Introductionmentioning

confidence: 99%

Lack of inhibitory effects of the anti‐fibrotic drug imatinib on endothelial cell functions in vitro and in vivo

Venalis

Maurer

Akhmetshina

et al. 2009

J Cellular Molecular Medi

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Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by microangiopathy with progressive loss of capillaries and tissue fibrosis. Imatinib exerts potent anti-fibrotic effects and is currently evaluated in clinical trials. The aim of the present study was to exclude that the anti-fibrotic effects of imatinib are complicated by inhibitory effects on endothelial cell functions, which might augment vascular disease in SSc. Endothelial cells and mice were treated with pharmacologically relevant concentrations of imatinib. The expression of markers of vascular activation was assessed with real-time PCR. Proliferation was analysed with the cell counting experiments and the MTT assay. Apoptosis was quantified with caspase 3 assays, annexin V in vitro and with TUNEL staining in vivo. Migration was studied with scratch and transwell assays. Tube forming was investigated with the matrigel assay. Imatinib did not alter the expression of markers of vascular activation. Imatinib did not increase the percentage of annexin V positive cells or the activity of caspase 3. No reduction in proliferation or metabolic activity of endothelial cells was observed. Imatinib did not affect migration of endothelial cells and did not reduce the formation of capillary tubes. Consistent with the in vitro data, no difference in the number of apoptotic endothelial cells was observed in vivo in mice treated with imatinib. Imatinib does not inhibit activation, viability, proliferation, migration or tube forming of endothelial cells in vitro and in vivo. Thus, treatment with imatinib might not augment further endothelial cell damage in SSc.

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“…c-Abl, a non-receptor tyrosine kinase, has recently been shown to be an important mediator of TGF-b signaling [8].…”

Section: Discussionmentioning

confidence: 99%

“…C-Abl has been newly identified as a downstream mediator of TGF-b1 signaling [34]. Imatinib mesylate, a small molecule tyrosine kinase inhibitor, has been shown to decrease the TGF-b1 stimulation of collagen expression both in vitro and in vivo [8,10,33]. Imatinib mesylate inhibits the tyrosine kinases c-Abl and c-kit and also disrupts platelet-derived growth factor (PDGF) signaling by blocking the tyrosine kinase activity of PDGF receptors [1,13].…”

Section: Introductionmentioning

confidence: 99%

Attenuation of fibrosis with selective inhibition of c-Abl by siRNA in systemic sclerosis dermal fibroblasts

et al. 2014

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Cellular abelson (c-Abl), a non-receptor tyrosine kinase, is an important molecule in the pathogenesis of systemic sclerosis. There have been reports of beneficial effects of pharmacological tyrosine kinase inhibitors, such as imatinib mesylate, on fibrosis. However, these inhibitors affect multiple tyrosine kinases including c-Abl, c-kit, and platelet-derived growth factor receptor. The effects of selective inhibition of c-Abl using small interfering RNA (siRNA) on dermal fibrosis have not yet been explored. The aim of this study is to evaluate whether specific inhibition of c-Abl by siRNA can influence the transforming growth factor-β1 (TGF-β1)-induced fibrotic responses. Dermal fibroblasts from systemic sclerosis patients and healthy controls were transfected with c-Abl siRNA. The expression levels of collagen type I, fibronectin, connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA) were measured at both the mRNA and protein levels in the absence or presence of TGF-β1 pro-fibrotic cytokine. In healthy dermal fibroblasts, the expression of collagen type 1, fibronectin, α-SMA, and CTGF mRNAs and proteins that were upregulated after stimulation with TGF-β1 was markedly decreased by c-Abl siRNA. Silencing of c-Abl via siRNA efficiently reduced the basal synthesis of collagen type I, fibronectin, α-SMA, and CTGF mRNAs and proteins in systemic sclerosis fibroblasts, but it had no effect on the baseline expression of these genes and proteins in healthy dermal fibroblasts. In conclusion, specific c-Abl gene silencing using siRNA effectively reduced fibrosis-related gene expression. Inhibition of c-Abl by siRNA may be a potential therapeutic approach for fibrotic diseases such as systemic sclerosis.

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Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis

Cited by 264 publications

References 49 publications

Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study

Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study

Lack of inhibitory effects of the anti‐fibrotic drug imatinib on endothelial cell functions in vitro and in vivo

Attenuation of fibrosis with selective inhibition of c-Abl by siRNA in systemic sclerosis dermal fibroblasts

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