Cardiotoxicity of the cancer therapeutic agent imatinib mesylate

Kerkelä, Risto; Grazette, Luanda; Yacobi, Rinat; Iliescu, Cezar; Patten, Richard D.; Beahm, Cara; Walters, Brian; Shevtsov, Sergey; Pesant, Stéphanie; Clubb, Fred J.; Rosenzweig, Anthony; Salomon, Robert N.; Etten, Richard A. Van; Alroy, Joseph; Durand, Jean Bernard; Force, Thomas

doi:10.1038/nm1446

Cited by 1,056 publications

(753 citation statements)

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“…However, a very recent report described 10 patients who developed congestive heart failure while being treated with imatinib mesylate (31), indicating that patients must be closely monitored for rare side effects.…”

Section: Discussionmentioning

confidence: 99%

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Distler¹,

Jüngel²,

Huber³

et al. 2007

Arthritis & Rheumatism

363

273

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Objective. Imatinib mesylate is a clinically welltolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor ␤ (TGF␤) and platelet-derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc).Methods. The expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real-time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycininduced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo.Results. Imatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose-dependent manner. The induction of ECM proteins after stimulation with TGF␤ and PDGF was also strongly and dose-dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects. Conclusion. These data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc.

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Section: Discussionmentioning

confidence: 99%

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Distler¹,

Jüngel²,

Huber³

et al. 2007

Arthritis & Rheumatism

363

273

View full text Add to dashboard Cite

show abstract

“…Side effects such as edema, myalgias, nausea, vomiting, anemia, leukopenia, thrombocytopenia, or increased levels of liver transaminases did not occur. There were also no signs of cardiomyopathy noted on echocardiograms and no signs of imatinib mesylate-induced pneumonitis (12,13).…”

Section: Case Reportmentioning

confidence: 91%

Treatment of pulmonary fibrosis for twenty weeks with imatinib mesylate in a patient with mixed connective tissue disease

Distler¹,

Manger²,

Spriewald³

et al. 2008

Arthritis & Rheumatism

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Interstitial lung disease, which is common in patients with mixed connective tissue disease (MCTD), can progress to severe pulmonary fibrosis. The tyrosine kinase inhibitor imatinib mesylate has recently been shown to prevent experimental pulmonary, dermal, and renal fibrosis. Our patient, a 64‐year‐old woman with MCTD and rapidly progressive pulmonary fibrosis, presented with rapid deterioration despite treatment with immunosuppressants. During 20 weeks of treatment with imatinib mesylate at 400 mg/day, our patient improved significantly according to several outcome measures, including New York Heart Association classification, diffusing capacity for carbon monoxide, 6‐minute walking distance, arterial oxygen pressure, and reduction of ground‐glass opacities seen on high‐resolution computed tomography. No adverse effects of imatinib mesylate were observed. These findings suggest that imatinib mesylate might be effective in patients with fibrotic diseases and warrant the initiation of larger clinical studies on the safety and efficacy of imatinib mesylate in connective tissue diseases.

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“…Examination of the release of adenylate kinase from ruptured cells into the cell culture medium was carried out with bioluminescent ToxiLight® Bioassay kit (Lonza Rockland Inc, Rockland, ME, USA) kit according to manufacturer's instructions (Kerkela et al, 2006).…”

Section: Cell Death Assaysmentioning

confidence: 99%

Distinct regulation of B-type natriuretic peptide transcription by p38 MAPK isoforms

Koivisto

Kaikkonen

Tokola

et al. 2011

Molecular and Cellular Endocrinology

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Persistent controversy underlies the functional roles of specific p38 MAPK isoforms in cardiac biology and regulation of hypertrophy-associated genes. Here we show that adenoviral gene transfer of p38β but not p38α increased B-type natriuretic peptide (BNP) mRNA levels in vitro as well as atrial natriuretic peptide mRNA levels both in vitro and in vivo. Overexpression of p38α, in turn, augmented the expression fibrosis-related genes connective tissue growth factor, basic fibroblast growth factor and matrix metalloproteinase-9 both in vitro and in vivo. p38β-induced BNP transcription was diminished by mutation of GATA-4 binding site, whereas overexpression of MKK6b, an upstream regulator of p38α and p38β, activated BNP transcription through both GATA-4 and AP-1. Overexpression of MKK3, upstream regulator of p38α, induced BNP transcription independently from AP-1 and GATA-4. These data provide new evidence for diversity in downstream targets and functional roles of p38 pathway kinases in regulation of hypertrophy-associated cardiac genes.

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Cardiotoxicity of the cancer therapeutic agent imatinib mesylate

Cited by 1,056 publications

References 50 publications

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Treatment of pulmonary fibrosis for twenty weeks with imatinib mesylate in a patient with mixed connective tissue disease

Distinct regulation of B-type natriuretic peptide transcription by p38 MAPK isoforms

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