The tyrosine kinase inhibitor dasatinib effectively blocks PDGF-induced orbital fibroblast activation

Sita Virakul, Virgil A S H Dalm, Dion Paridaens, Willem A van den Bosch, Nattiya Hirankarn, P Martin van Hagen, Willem A Dik

Research output: Contribution to journalArticleResearchpeer-review

Abstract

BACKGROUND: Graves' ophthalmopathy (GO) remains hard to treat. Excessive orbital fibroblast activation by platelet-derived growth factor (PDGF)-BB contributes to GO. The tyrosine kinase inhibitors (TKIs) imatinib mesylate and dasatinib both target PDGF-receptor tyrosine kinase activity, albeit with a different potency. We compared the efficacy of these TKIs on PDGF-BB-induced proliferation, and on cytokine and hyaluronan production by orbital fibroblasts. Also the capacity of dasatinib to suppress GO-associated gene expression in orbital tissue was examined.

METHODS: Orbital fibroblasts from four GO patients and five control subjects were used. The efficacy of the two TKIs was tested by: 1) pre-incubating orbital fibroblasts overnight with different TKI concentrations, followed by 24 h stimulation with PDGF-BB, 2) adding TKI and PDGF-BB simultaneously to the orbital fibroblasts in 24 h cultures. Proliferation was assessed by colorimetric assay. Hyaluronan and cytokine production were measured by ELISA. Furthermore, orbital tissue was obtained from a patient with active GO, and the effect of dasatinib on the expression levels of HAS2-, CCL2-, IL6-, and IL8-mRNA expression was examined by real-time quantitative PCR.

RESULTS: Pre-incubation of orbital fibroblasts with imatinib mesylate or dasatinib resulted in significant and dose-dependent inhibition of PDGF-BB-induced orbital fibroblast proliferation, and hyaluronan and cytokine production. Dasatinib exhibited these effects at far lower concentrations. The same results were observed in the setting where TKI and PDGF-BB treatments were commenced simultaneously. In orbital tissue from active GO, dasatinib significantly suppressed HAS2-, CCL2-, IL6- and IL8-mRNA levels.

CONCLUSION: Dasatinib may be a promising alternative to high-dose steroids in the treatment of GO.

Original languageEnglish
Pages (from-to)1101-9
Number of pages9
JournalGraefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie
Volume252
Issue number7
DOIs
Publication statusPublished - Jul 2014

Keywords

  • Becaplermin
  • Benzamides/pharmacology
  • Cell Proliferation/drug effects
  • Cells, Cultured
  • Chemokine CCL2/genetics
  • Dasatinib
  • Dose-Response Relationship, Drug
  • Fibroblasts/drug effects
  • Gene Expression Regulation/physiology
  • Glucuronosyltransferase/genetics
  • Graves Ophthalmopathy/drug therapy
  • Humans
  • Hyaluronan Synthases
  • Imatinib Mesylate
  • Interleukin-6/genetics
  • Interleukin-8/genetics
  • Orbit/pathology
  • Piperazines/pharmacology
  • Protein Kinase Inhibitors/pharmacology
  • Protein-Tyrosine Kinases/antagonists & inhibitors
  • Proto-Oncogene Proteins c-sis/antagonists & inhibitors
  • Pyrimidines/pharmacology
  • RNA, Messenger/genetics
  • Thiazoles/pharmacology

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