Abstract
We compared the antitumor activities of the multitargeted tyrosine kinase inhibitors imatinib, sorafenib, and sunitinib to determine which inhibitor is best suited to be used for the treatment of acute myelogenous leukemia (AML). In nine human AML cell lines, sorafenib and sunitinib were more potent inhibitors of cellular proliferation than imatinib (IC50, 0.27 to >40, 0.002-9.1, and 0.007-13 micromol/L for imatinib, sorafenib, and sunitinib, respectively). Sorafenib and sunitinib were potent inhibitors of cells with fms-like tyrosine kinase 3 internal tandem duplication (IC50, 2 and 7 nmol/L) and c-KIT N822K mutations (IC50, 23 and 40 nmol/L). In four cell lines (MV4-11, Kasumi-1, KG-1, and U937) that spanned a range of drug sensitivities, sorafenib and sunitinib had similar activity in apoptosis and cell cycle assays, except that sunitinib did not promote apoptosis in U937 cells. Both drugs inhibited mitogen-activated protein kinase signaling but had no effect on AKT signaling in most of the cell lines tested. Sorafenib was substantially more bound than sunitinib in human plasma (unbound fraction, 0.59% versus 8.4%) and cell culture medium (unbound fraction, 1.3% versus 39%), indicating that sorafenib was more potent than sunitinib and that unbound sorafenib concentrations with activity against most AML cell lines are achievable in vivo. There was more intracellular accumulation of sorafenib than of sunitinib and imatinib in AML cells. Between 1 and 10 micromol/L, sorafenib inhibited the proliferation of six of nine primary AML blast samples by > or =50%. Our results highlight the pharmacologic features of sorafenib that may provide it an advantage in the treatment of AML.
Highlights
Receptor tyrosine kinases such as c-KIT, fms-like tyrosine kinase 3 (FLT3), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor play important roles in regulating cell proliferation, differentiation, and survival by activating downstream effectors such as signal transducers and activators of transcription (STAT), protein kinase B/AKT, and extracellular signal-regulated kinase 1/2 (ERK1/2; refs. 1 – 4)
Sorafenib and sunitinib were more potent than imatinib against Kasumi-1 cells with a c-KIT N822K mutation: with IC50 of 40 and 23 nmol/L for sorafenib and sunitinib, respectively, versus 270 nmol/L for imatinib (Table 1)
To relate in vitro IC50 for inhibiting cellular proliferation to exposures that are achievable in vivo, the unbound fractions of imatinib, sorafenib, and sunitinib in cell culture medium and human plasma were determined by equilibrium dialysis
Summary
Receptor tyrosine kinases such as c-KIT, fms-like tyrosine kinase 3 (FLT3), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor play important roles in regulating cell proliferation, differentiation, and survival by activating downstream effectors such as signal transducers and activators of transcription (STAT), protein kinase B/AKT, and extracellular signal-regulated kinase 1/2 (ERK1/2; refs. 1 – 4). Disruption of cell growth and survival because of aberrant activation of receptor tyrosine kinases may promote leukemogenesis in acute myelogenous leukemia FLT3 mutations occur in about one third of patients with AML and can be (a) internal tandem duplication of 3 to 400 bp in the juxtamembrane domain (in 23% of patients) and (b) point mutations mainly involving aspartic acid 835 in the second tyrosine kinas domain Activating mutations in c-KIT involving the extracellular or second tyrosine kinase domains have been reported in AML, predominantly in patients with t(8;21) and inv[16] The presence of FLT3 internal tandem duplication and c-KIT mutations is associated with poor prognosis and survival in adults and children with AML [10, 11].
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