Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway.
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.
Department of Hematology, Graduate School of Medicine, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
Tetsuya
T
Kurosu
Manabu
M
Ohki
Nan
N
Wu
Hiroyuki
H
Kagechika
Osamu
O
Miura
D000098:Acetophenones / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000494:pharmacology*; D001578:Benzopyrans / Q000008:administration & dosage; D001713:Biphenyl Compounds / Q000008:administration & dosage; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007377:Interleukin-3 / Q000494:pharmacology; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives; D009596:Nitrophenols / Q000008:administration & dosage; D010671:Phenylurea Compounds; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011719:Pyrazines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D000077157:Sorafenib; D013449:Sulfonamides / Q000008:administration & dosage
C501332:ABT-737; D000098:Acetophenones; D001549:Benzamides; D001557:Benzenesulfonates; D001578:Benzopyrans; D001713:Biphenyl Compounds; D001897:Boronic Acids; D007377:Interleukin-3; D009596:Nitrophenols; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D009536:Niacinamide; D000069286:Bortezomib; D000068877:Imatinib Mesylate; D000077157:Sorafenib; C085746:rottlerin; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D020169:Caspases