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Dasatinib Modulates Invasive and Migratory Properties of Canine Osteosarcoma and has Therapeutic Potential in Affected Dogs.

Marley K, Gullaba J, Seguin B, Gelberg HB, Helfand SC - Transl Oncol (2015)

Bottom Line: HGF induces secretion of different forms of MMP in different cell lines.The HGF-driven increase in viability and metastatic behaviors we observed are more uniformly inhibited by dasatinib.These observations suggest a potential clinical benefit of adjuvant dasatinib treatment for dogs with OS.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences Oregon State University, 105 Magruder Hall, Corvallis OR, 97331, USA. Electronic address: kevin.marley@oregonstate.edu.

No MeSH data available.


Related in: MedlinePlus

MTS assays with tyrosine kinase inhibitors and HGF. Viability of HGF-stimulated cells was inhibited at low concentrations by dasatinib (top panels) but not by crizotinib (bottom panels). *Difference between HGF-treated and control at the same TKI concentration (P ≤ .05). IC50 values for dasatinib were 0.1 nM in controls and 32 nM in cells incubated with HGF in the COS cell line. These values were 0.3 nM and 112 nM in the Clone-4 cell line, respectively. IC50 values for crizotinib were 340 nM and 357 for COS controls and HGF-treated cells and was not reached in the Clone-4 cell line.
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f0015: MTS assays with tyrosine kinase inhibitors and HGF. Viability of HGF-stimulated cells was inhibited at low concentrations by dasatinib (top panels) but not by crizotinib (bottom panels). *Difference between HGF-treated and control at the same TKI concentration (P ≤ .05). IC50 values for dasatinib were 0.1 nM in controls and 32 nM in cells incubated with HGF in the COS cell line. These values were 0.3 nM and 112 nM in the Clone-4 cell line, respectively. IC50 values for crizotinib were 340 nM and 357 for COS controls and HGF-treated cells and was not reached in the Clone-4 cell line.

Mentions: Low-concentration dasatinib, but not crizotinib, reduced the viability of serum-starved OS cells (Figure 3). This effect was blocked by HGF in both cell lines at TKI concentrations less than 100 nM. The protective effect of HGF was lost at dasatinib concentrations greater than 100 nM. Crizotinib was less effective and only slightly inhibited viability of the COS cells at concentrations of 100 nM and greater (Figure 3). Crizotinib had no effect on the Clone-4 cell line at concentrations less than 3 μM, which was the highest concentration deemed reasonable in this study. No significant changes in cell death or apoptosis were attributable to 20-nM dasatinib incubation (Figure 4), which was the concentration used for the migration and invasion assays. Under serum-starved conditions, the dasatinib IC50 values for the COS cell line were 0.1 nM for the untreated and 32 nM for the HGF-treated cells. Dasatinib was similarly effective in the Clone-4 cell line, with IC50s of 0.3 nM and 112 nM in the untreated and treated cells, respectively. The crizotinib IC50s for the COS cells were 340 nM and 357 nM for the untreated and HGF-treated cells, respectively; and no IC50 values were observed for crizotinib in the Clone-4 cell because the drug did not effectively reduce viability in these cells.


Dasatinib Modulates Invasive and Migratory Properties of Canine Osteosarcoma and has Therapeutic Potential in Affected Dogs.

Marley K, Gullaba J, Seguin B, Gelberg HB, Helfand SC - Transl Oncol (2015)

MTS assays with tyrosine kinase inhibitors and HGF. Viability of HGF-stimulated cells was inhibited at low concentrations by dasatinib (top panels) but not by crizotinib (bottom panels). *Difference between HGF-treated and control at the same TKI concentration (P ≤ .05). IC50 values for dasatinib were 0.1 nM in controls and 32 nM in cells incubated with HGF in the COS cell line. These values were 0.3 nM and 112 nM in the Clone-4 cell line, respectively. IC50 values for crizotinib were 340 nM and 357 for COS controls and HGF-treated cells and was not reached in the Clone-4 cell line.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4562978&req=5

f0015: MTS assays with tyrosine kinase inhibitors and HGF. Viability of HGF-stimulated cells was inhibited at low concentrations by dasatinib (top panels) but not by crizotinib (bottom panels). *Difference between HGF-treated and control at the same TKI concentration (P ≤ .05). IC50 values for dasatinib were 0.1 nM in controls and 32 nM in cells incubated with HGF in the COS cell line. These values were 0.3 nM and 112 nM in the Clone-4 cell line, respectively. IC50 values for crizotinib were 340 nM and 357 for COS controls and HGF-treated cells and was not reached in the Clone-4 cell line.
Mentions: Low-concentration dasatinib, but not crizotinib, reduced the viability of serum-starved OS cells (Figure 3). This effect was blocked by HGF in both cell lines at TKI concentrations less than 100 nM. The protective effect of HGF was lost at dasatinib concentrations greater than 100 nM. Crizotinib was less effective and only slightly inhibited viability of the COS cells at concentrations of 100 nM and greater (Figure 3). Crizotinib had no effect on the Clone-4 cell line at concentrations less than 3 μM, which was the highest concentration deemed reasonable in this study. No significant changes in cell death or apoptosis were attributable to 20-nM dasatinib incubation (Figure 4), which was the concentration used for the migration and invasion assays. Under serum-starved conditions, the dasatinib IC50 values for the COS cell line were 0.1 nM for the untreated and 32 nM for the HGF-treated cells. Dasatinib was similarly effective in the Clone-4 cell line, with IC50s of 0.3 nM and 112 nM in the untreated and treated cells, respectively. The crizotinib IC50s for the COS cells were 340 nM and 357 nM for the untreated and HGF-treated cells, respectively; and no IC50 values were observed for crizotinib in the Clone-4 cell because the drug did not effectively reduce viability in these cells.

Bottom Line: HGF induces secretion of different forms of MMP in different cell lines.The HGF-driven increase in viability and metastatic behaviors we observed are more uniformly inhibited by dasatinib.These observations suggest a potential clinical benefit of adjuvant dasatinib treatment for dogs with OS.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences Oregon State University, 105 Magruder Hall, Corvallis OR, 97331, USA. Electronic address: kevin.marley@oregonstate.edu.

No MeSH data available.


Related in: MedlinePlus