The tyrosine kinase inhibitor dasatinib effectively blocks PDGF-induced orbital fibroblast activation
Graefe's Archive for Clinical and Experimental Ophthalmology , Volume 252 - Issue 7 p. 1101- 1109
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.
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|Graefe's Archive for Clinical and Experimental Ophthalmology|
|Organisation||Department of Ophthalmology|
Virakul, S, Dalm, V.A.S.H, Paridaens, A.D.A, van den Bosch, W.A, Hirankarn, N, van Hagen, P.M, & Dik, W.A. (2014). The tyrosine kinase inhibitor dasatinib effectively blocks PDGF-induced orbital fibroblast activation. Graefe's Archive for Clinical and Experimental Ophthalmology, 252(7), 1101–1109. doi:10.1007/s00417-014-2674-7