Abstract
Although the BCR/ABL tyrosine kinase inhibitor imatinib is highly effective for treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia, relapse with emerging imatinib resistance mutations in the BCR/ABL kinase domain poses a significant problem. Here, we show that the multikinase inhibitor sorafenib inhibits proliferation and induces apoptosis at much lower concentrations in Ton.B210 cells when driven by inducibly expressed BCR/ABL than when driven by interleukin-3. The increased sensitivity to sorafenib was also observed in cells inducibly expressing BCR/ABL with the imatinib-resistant E255K or T315I mutation. Sorafenib-induced apoptosis in these cells and Ph+ leukemic cells was synergistically enhanced by rottlerin, bortezomib, or ABT-737 and inhibited by the pan-caspase inhibitor BOC-d-fmk or the overexpression of Bcl-XL. It was further revealed that sorafenib activates Bax and caspase-3 and reduces mitochondrial membrane potential specifically in BCR/ABL-driven cells. Sorafenib also inhibited BCR/ABL-induced tyrosine phosphorylation of its cellular substrates and its autophosphorylation in Ton.B210. It was finally shown that sorafenib inhibits the kinase activity of BCR/ABL as well as its E255K and T315I mutants in in vitro kinase assays. These results indicate that sorafenib induces apoptosis of BCR/ABL-expressing cells, at least partly, by inhibiting BCR/ABL to activate the mitochondria-mediated apoptotic pathway. Thus, sorafenib may provide an effective therapeutic measure to treat Ph+ leukemias, particularly those expressing the T315I mutant, which is totally resistant to imatinib and the second generation BCR/ABL inhibitors.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetophenones / administration & dosage
-
Antineoplastic Combined Chemotherapy Protocols / pharmacology
-
Apoptosis / drug effects*
-
Apoptosis / physiology
-
Benzamides
-
Benzenesulfonates / administration & dosage
-
Benzenesulfonates / pharmacology*
-
Benzopyrans / administration & dosage
-
Biphenyl Compounds / administration & dosage
-
Boronic Acids / administration & dosage
-
Bortezomib
-
Caspases / metabolism
-
Drug Resistance, Neoplasm
-
Drug Synergism
-
Enzyme Activation / drug effects
-
Fusion Proteins, bcr-abl / antagonists & inhibitors*
-
Fusion Proteins, bcr-abl / biosynthesis
-
Fusion Proteins, bcr-abl / genetics
-
Humans
-
Imatinib Mesylate
-
Interleukin-3 / pharmacology
-
K562 Cells
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
-
Mitochondria / drug effects*
-
Mitochondria / physiology
-
Mutation
-
Niacinamide / analogs & derivatives
-
Nitrophenols / administration & dosage
-
Phenylurea Compounds
-
Piperazines / administration & dosage
-
Piperazines / pharmacology
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
-
Protein Kinase Inhibitors / administration & dosage
-
Protein Kinase Inhibitors / pharmacology
-
Protein-Tyrosine Kinases / antagonists & inhibitors*
-
Protein-Tyrosine Kinases / biosynthesis
-
Pyrazines / administration & dosage
-
Pyridines / administration & dosage
-
Pyridines / pharmacology*
-
Pyrimidines / pharmacology
-
Sorafenib
-
Sulfonamides / administration & dosage
Substances
-
ABT-737
-
Acetophenones
-
Benzamides
-
Benzenesulfonates
-
Benzopyrans
-
Biphenyl Compounds
-
Boronic Acids
-
Interleukin-3
-
Nitrophenols
-
Phenylurea Compounds
-
Piperazines
-
Protein Kinase Inhibitors
-
Pyrazines
-
Pyridines
-
Pyrimidines
-
Sulfonamides
-
Niacinamide
-
Bortezomib
-
Imatinib Mesylate
-
Sorafenib
-
rottlerin
-
Protein-Tyrosine Kinases
-
Fusion Proteins, bcr-abl
-
Caspases