Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway.

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.

• Authors: Tetsuya Kurosu, Manabu Ohki, Nan Wu, Hiroyuki Kagechika, Osamu Miura
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 9 Pg. 3927-36 (May 01 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19366808 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Acetophenones (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects, physiology)
• Benzamides
• Benzenesulfonates (administration & dosage, 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, biosynthesis, genetics)
• Humans
• Imatinib Mesylate
• Interleukin-3 (pharmacology)
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism, pathology)
• Mitochondria (drug effects, physiology)
• Mutation
• Niacinamide (analogs & derivatives)
• Nitrophenols (administration & dosage)
• Phenylurea Compounds
• Piperazines (administration & dosage, pharmacology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism, pathology)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors, biosynthesis)
• Pyrazines (administration & dosage)
• Pyridines (administration & dosage, pharmacology)
• Pyrimidines (pharmacology)
• Sorafenib
• Sulfonamides (administration & dosage)