論文 - 詳細
| RRC ID | 37627 |
|---|---|
| 著者 | Kurosu T, Ohki M, Wu N, Kagechika H, Miura O. |
| タイトル | Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway. |
| ジャーナル | Cancer Res |
| 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. |
| 巻・号 | 69(9) |
| ページ | 3927-36 |
| 公開日 | 2009-5-1 |
| DOI | 10.1158/0008-5472.CAN-08-2978 |
| PII | 0008-5472.CAN-08-2978 |
| PMID | 19366808 |
| MeSH | 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 |
| IF | 9.727 |
| 引用数 | 40 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | KU812(RCB0495) K562 |