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Linda Musil; Multikinase Inhibitors as Potential Anti-PCO Therapeutics . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3211.
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© ARVO (1962-2015); The Authors (2016-present)
Clinically deleterious fibrotic-type posterior capsule opacification (PCO) is caused by the accumulation of myofibroblastic cells at the posterior of the lens capsule. Our goal is to develop pharmacological therapies to prevent this vision-disrupting complication of cataract surgery.
Expression of established markers of epithelial-mesenchymal transition (EMT) in serum-free cultures of primary chick lens epithelial cells (DCDMLs) was assessed by Western blotting or immunocytochemistry. Activation of signal transduction pathways was measured using phospho-specific antibodies. Cell migration was assessed using an inverted coverslip assay, and cell proliferation with MTT.
We previously showed that > 0.4 ng/ml TGFB induces conversion of lens epithelial cells into myofibroblasts in DCDMLs. We report here that EMT in this system is blocked by DCC-2036, a multikinase small molecule inhibitor currently in clinical trials for non-ocular cancers. DCC-2036 also inhibited TGFB-induced cell migration. Both findings may be attributable to DCC-2036’s ability to block activation of ERK MAP kinase by TGFB; canonical Smad2/3 signaling was not affected. DCC-2036 did not affect cell viability, nor cause the cells to loose their epithelial phenotype. Other experiments showed that DCC-2036 prevented FGF from inducing cell proliferation, in keeping with the drug’s known inhibitory effect on FGF receptor activity. A single, one-hour exposure to 10 uM DCC-2036 was sufficient to block growth factor-induced conversion of lens epithelial cells into myofibroblasts, as well as cell migration and proliferation.
Together, these results raise the possibility that a one-time treatment with a small molecule multikinase inhibitor could block all three processes that lead to fibrotic PCO.
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