Our data suggest that the active Src pathway is not crucial for m

Our data suggest that the active Src pathway is not crucial for myxoid liposarcoma survival and that monotherapy Temsirolimus structure with dasatinib is no suitable option for treatment, although the additional effect of dasatinib in vivo through inhibition of angiogenesis is not encountered Inhibitors,Modulators,Libraries here. Combinations of different drugs have been shown Inhibitors,Modulators,Libraries to act synergistically in many tumors and combination drug therapy is commonly used in can cer treatment. Recently, a synergistic effect of dasati nib when combined with other drugs has been described in colorectal carcinoma. Since we showed NF kappaB and Src to be the two most active pathways we studied the effect of combination of dasati nib and TBB and we found a enhanced effect on cell via bility of myxoid liposarcoma cells in vitro.

To be more specific L1357 cells show 80% viability at maximum dasatinib dose, whereas viability was only 5% at lower concentration of dasatinib at IC50 for TBB. However, it was not possible to calculate if this enhancement was also a true synergistic effect as IC50 values for dasatinib could not be calculated. IC50 values for TBB could be calculated Inhibitors,Modulators,Libraries for most primary cultures and cell lines, but not for L1187 and L1434. Though cell line 1765 92 responded well to TBB treatment, no enhancement could be observed upon addition of dasatinib, which might be related to Inhibitors,Modulators,Libraries a relative resistance of 1765 92 cells to dasati nib as also visible from figure 3A.

Future experiments, for instance studying the changes at the kinome Inhibitors,Modulators,Libraries level upon dasatinib treatment may reveal why dasatinib is not effective as a monotherapy but is effective in combi nation with TBB, and what might be the exact under lying mechanism why 1765 92 myxoid liposarcoma cells showed resistance for dasatinib necessary treatment and thereby the absence of enhancement in combination treatment as was observed for the other cell line and primary cultures. Conclusion In conclusion our results indicate that the NF kappaB and Src pathway include the most active kinases in myx oid liposarcoma, and inhibition of casein kinase 2 and thereby interference with kinases associated with the NF kappaB pathway decreases cell viability in vitro, the effect of which can be enhanced by inhibiting src sig nalling using dasatinib. Methods Reagents Dasatinib was obtained from Bristol Myers Squibb and TBB from Calbiochem. Both drugs were dissolved in Dimethylsulfoxide. Cell cultures and cell lines The two myxoid liposarcoma cell lines 402 91 and 1765 92, and gastro intestinal stroma cell tumor cell line were kindly provided by Prof. Dr. P. Aman and Prof. Dr. J. Fletcher respectively. Jurkat and HeLa cell lines were used as positive controls for Western blotting.

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