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. 2011 Feb;1(2):e2.
doi: 10.1038/bcj.2011.1. Epub 2011 Feb 4.

The tyrosine kinase inhibitor dasatinib (SPRYCEL) inhibits chondrocyte activity and proliferation

K Vandyke, S Fitter, A C W Zannettino

The tyrosine kinase inhibitor dasatinib (SPRYCEL) inhibits chondrocyte activity and proliferation

K Vandyke et al. Blood Cancer J. 2011 Feb.
No abstract available

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Figures

Figure 1
Figure 1
The proximal tibial growth plate is thinned in dasatinib-treated animals. Nine-month-old female Sprague–Dawley rats were treated for 12 weeks with dasatinib (5 mg/kg per day) or vehicle (10% DMSO/90% PEG 300). Six animals per group were humanely killed after 4, 8 and 12 weeks of treatment and right tibiae were collected for histological analysis. Samples were embedded in paraffin and 5-μm sections were stained with safranin O/fast green. Growth plate thickness was measured at five equidistant points across the centre of the growth plate. Box plots depict median, 25th and 75th percentiles±range (n=4–6). *P<0.05 (Student's t-tests).
Figure 2
Figure 2
Dasatinib inhibits cell proliferation and activity in ATDC5 cultures. (a) ATDC5 cells (1.56 × 104 cells per cm2) were seeded in 96-well plates in α-MEM with 10% fetal bovine serum, 2 m-glutamine, 1 m sodium pyruvate, 15 m HEPES, 50 U/ml penicillin, 50 μg/ml streptomycin and 100 μ ascorbate (c-α-MEM) and were cultured overnight to allow the cells to adhere. The cells were then treated with dasatinib or vehicle (0.05% DMSO) for the indicated periods of time before the relative number of cells per well were determined by WST-1 assay. Graphs depict mean±range of two representative experiments. *P<0.05 relative to vehicle control at each time-point (one-way ANOVA with Dunnett's post-tests). (b) ATDC5 cells (1.56 × 105 cells per cm2) were treated with rhTGF-β1 (10 ng/ml) and the indicated doses of dasatinib or 0.05% DMSO vehicle for 48 h. GAG levels were then quantitated and normalised to DNA content to determine relative GAG production per cell. Graphs depict mean±s.e.m. of triplicate wells of a representative experiment, normalised to the rhTGF-β1-treated vehicle control. *P<0.05 relative to the rhTGF-β1-treated vehicle control (one-way ANOVA with Dunnett's post tests). (c) ATDC5 cells were cultured overnight at 1.56 × 105 cells per cm2 in six-well plates in c-α-MEM. The cells were serum starved by overnight incubation in serum-free α-MEM. The cells were pre-treated with dasatinib or 0.05% DMSO for 2 h before stimulation with rhPDGF-BB (10 ng/ml) for 5 min. Cell lysates (30 μg per lane) were resolved through a 10% sodium dodecyl sulphate-PAGE gel and the phosphorylated forms of Akt (p-Akt) and ERK1/2 (p-ERK1/2), as well as total HSP90, were detected using specific antibodies. Images from a representative of two experiments are shown. (d) Graphs indicate the pixel intensity for p-Akt and p-ERK1/2, relative to HSP90, normalised to vehicle controls. (e) ATDC5 cells were treated with 40 n dasatinib or vehicle (0.05% DMSO) supplemented, where indicated, with 10 ng/ml rhPDGF-BB. After 6 days, the relative number of cells per well was determined by WST-1 assay. Graphs depict mean±range of two representative experiments, normalised to vehicle control. (f) ATDC5 cells (cultured as in b) were then treated with vehicle (V) or 40 n dasatinib (D) with or without 100 ng/ml rhPDGF-BB. After 48 h, GAG levels and DNA content were quantitated and GAG production per cell was calculated. Graphs depict mean±s.e.m. of triplicate wells of a representative experiment, normalised to vehicle controls. *P<0.05, as indicated (Student's t-tests).
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