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

Sita Virakul1, Virgil A S H Dalm, Dion Paridaens

  • 1Department of Immunology, Erasmus MC, University Medical Center, PO Box 2040, 3000, CA, Rotterdam, The Netherlands.

Graefe'S Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie
|May 31, 2014
PubMed
Abstract

Insights

Dasatinib effectively inhibits platelet-derived growth factor-BB (PDGF-BB) in Graves' ophthalmopathy (GO) fibroblasts, offering a potential alternative to steroids. This tyrosine kinase inhibitor (TKI) reduces fibroblast proliferation and associated gene expression in GO orbital tissue.

Area of Science:

  • Ophthalmology
  • Endocrinology
  • Pharmacology

Background:

  • Graves' ophthalmopathy (GO) is challenging to treat, with fibroblast overactivation by platelet-derived growth factor (PDGF)-BB being a key factor.
  • Tyrosine kinase inhibitors (TKIs) imatinib mesylate and dasatinib target PDGF-receptor tyrosine kinase activity, but with differing potencies.

Purpose of the Study:

  • To compare the efficacy of imatinib mesylate and dasatinib in inhibiting PDGF-BB-induced orbital fibroblast proliferation.
  • To assess the impact of these TKIs on cytokine and hyaluronan production by orbital fibroblasts.
  • To examine dasatinib's capacity to suppress GO-associated gene expression in orbital tissue.

Main Methods:

  • Orbital fibroblasts from GO patients and controls were cultured and treated with TKIs (imatinib or dasatinib) and PDGF-BB.
  • Proliferation was measured using a colorimetric assay; hyaluronan and cytokine production were quantified via ELISA.
  • Gene expression (HAS2, CCL2, IL6, IL8 mRNA) in GO orbital tissue treated with dasatinib was analyzed by real-time quantitative PCR.

Main Results:

  • Both imatinib and dasatinib significantly inhibited PDGF-BB-induced fibroblast proliferation, hyaluronan, and cytokine production in a dose-dependent manner.
  • Dasatinib demonstrated these inhibitory effects at substantially lower concentrations compared to imatinib.
  • Simultaneous administration of TKIs and PDGF-BB yielded similar inhibitory results.
  • In GO orbital tissue, dasatinib significantly reduced the expression of HAS2, CCL2, IL6, and IL8 mRNA.

Conclusions:

  • Dasatinib effectively suppresses key pathways involved in Graves' ophthalmopathy pathogenesis.
  • Dasatinib shows promise as a potential therapeutic alternative to high-dose steroids for treating Graves' ophthalmopathy.

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