Comparison of the effects of two kinase inhibitors, sorafenib and dasatinib, on chronic lymphocytic leukemia cells.

BACKGROUND

With sorafenib displaying the highest affinities for Flt3, VEGFR (vascular endothelial growth factor receptor) and Raf and dasatinib for Abl and Src kinases, the profiles of kinases targeted by these inhibitors differ strongly.

MATERIALS AND

METHODS

Dose-dependent effects of the inhibitors on freshly isolated chronic lymphocytic leukemia (CLL) cells were assessed as increased phosphatidylserine exposure. Inhibition by sorafenib and dasatinib of survival and anti-apoptotic signaling in CLL cells was examined by Western blot analysis.

RESULTS

Sorafenib uniformly induced apoptosis in CLL lymphocytes with a concentration inhibiting by 50% (IC50) of 8 mM, whereas the response to dasatinib was heterogeneous with the onset of inhibition at submicromolar concentrations but with IC50 values below 25 mM in only a few samples. At the respective pharmacologically achievable plasma concentrations, the inhibitors showed more efficient apoptosis induction by sorafenib than by dasatinib and less than additive mutual enhancement in combination. Co-culture with the bone marrow stroma cell line HS-5 increased the viability of untreated CLL cells but did not protect from sorafenib-induced apoptosis.

CONCLUSIONS

Sorafenib or dasatinib displayed sigmoidal or saturation-type dose-response relationships for apoptosis induction, which were uniform or highly divergent, respectively, among individual CLL samples and therefore might complement each other in their clinical potential for CLL.