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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

Expression and protease activity of MMP2 in COS and Clone-4 cells exposed to HGF and crizotinib or dasatinib. (A) Cells were incubated overnight in R10 media (10% serum) or serum-free media with HGF ± TKI as indicated. Criz-20 and criz-40 indicate 20-nM and 40-nM incubation concentrations. The expression patterns between the two cell lines are quite different, with COS cells expressing the pro- and active form uniformly, whereas the Clone-4 cells expressed only the active form. The protease activity of active MMP2 was reduced by both crizotinib and dasatinib, with dasatinib appearing to be the more effective drug at these low concentrations.
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f0030: Expression and protease activity of MMP2 in COS and Clone-4 cells exposed to HGF and crizotinib or dasatinib. (A) Cells were incubated overnight in R10 media (10% serum) or serum-free media with HGF ± TKI as indicated. Criz-20 and criz-40 indicate 20-nM and 40-nM incubation concentrations. The expression patterns between the two cell lines are quite different, with COS cells expressing the pro- and active form uniformly, whereas the Clone-4 cells expressed only the active form. The protease activity of active MMP2 was reduced by both crizotinib and dasatinib, with dasatinib appearing to be the more effective drug at these low concentrations.

Mentions: This study assessed the effects of HGF on MMP-2 and MMP-9 secretion by OS cell lines and measured the ability of the TKIs dasatinib and crizotinib to block this secretion. We were surprised by the observation that MMP isoform production was dramatically different in the two OS cell lines. Beginning with MMP-2, secretion of the pro-form of MMP-2 was dramatically induced in the COS cells by serum-containing media; but this was not observed in the Clone-4 cells (Figure 6). Both the pro- and active forms of MMP-2 were produced in the presence of HGF in the COS cells, but HGF induced only the active form in the Clone-4 cells. The zymogram densitometry shows a dose–response relationship, with both TKIs suppressing secretion of the active form of MMP-2; however, this effect was more pronounced with dasatinib (Figure 6). The difference between the two cell lines was more pronounced with MMP-9 secretion versus that seen in MMP-2, as media from the COS cells produced a major band on the zymographs, whereas none was detected using media from the Clone-4 cell line. In this regard, the MMP-9 secretion was entirely dependent on HGF in the COS cells (Figure 7, MMP-9 data for Clone-4 are not shown). This HGF-induced MMP-9 secretion was suppressed in COS cells by coincubation with crizotinib but not dasatinib. Data shown are representative of three independent experiments (Figure 7).


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)

Expression and protease activity of MMP2 in COS and Clone-4 cells exposed to HGF and crizotinib or dasatinib. (A) Cells were incubated overnight in R10 media (10% serum) or serum-free media with HGF ± TKI as indicated. Criz-20 and criz-40 indicate 20-nM and 40-nM incubation concentrations. The expression patterns between the two cell lines are quite different, with COS cells expressing the pro- and active form uniformly, whereas the Clone-4 cells expressed only the active form. The protease activity of active MMP2 was reduced by both crizotinib and dasatinib, with dasatinib appearing to be the more effective drug at these low concentrations.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0030: Expression and protease activity of MMP2 in COS and Clone-4 cells exposed to HGF and crizotinib or dasatinib. (A) Cells were incubated overnight in R10 media (10% serum) or serum-free media with HGF ± TKI as indicated. Criz-20 and criz-40 indicate 20-nM and 40-nM incubation concentrations. The expression patterns between the two cell lines are quite different, with COS cells expressing the pro- and active form uniformly, whereas the Clone-4 cells expressed only the active form. The protease activity of active MMP2 was reduced by both crizotinib and dasatinib, with dasatinib appearing to be the more effective drug at these low concentrations.
Mentions: This study assessed the effects of HGF on MMP-2 and MMP-9 secretion by OS cell lines and measured the ability of the TKIs dasatinib and crizotinib to block this secretion. We were surprised by the observation that MMP isoform production was dramatically different in the two OS cell lines. Beginning with MMP-2, secretion of the pro-form of MMP-2 was dramatically induced in the COS cells by serum-containing media; but this was not observed in the Clone-4 cells (Figure 6). Both the pro- and active forms of MMP-2 were produced in the presence of HGF in the COS cells, but HGF induced only the active form in the Clone-4 cells. The zymogram densitometry shows a dose–response relationship, with both TKIs suppressing secretion of the active form of MMP-2; however, this effect was more pronounced with dasatinib (Figure 6). The difference between the two cell lines was more pronounced with MMP-9 secretion versus that seen in MMP-2, as media from the COS cells produced a major band on the zymographs, whereas none was detected using media from the Clone-4 cell line. In this regard, the MMP-9 secretion was entirely dependent on HGF in the COS cells (Figure 7, MMP-9 data for Clone-4 are not shown). This HGF-induced MMP-9 secretion was suppressed in COS cells by coincubation with crizotinib but not dasatinib. Data shown are representative of three independent experiments (Figure 7).

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