論文 - 詳細
| RRC ID | 38228 |
|---|---|
| 著者 | Kurosu T, Wu N, Oshikawa G, Kagechika H, Miura O. |
| タイトル | Enhancement of imatinib-induced apoptosis of BCR/ABL-expressing cells by nutlin-3 through synergistic activation of the mitochondrial apoptotic pathway. |
| ジャーナル | Apoptosis |
| Abstract |
The BCR/ABL tyrosine kinase inhibitor imatinib is highly effective for treatment of chronic myeloid leukemia (CML) and Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). However, relapses with emerging imatinib-resistance mutations in the BCR/ABL kinase domain pose a significant problem. Here, we demonstrate that nutlin-3, an inhibitor of Mdm2, inhibits proliferation and induces apoptosis more effectively in BCR/ABL-driven Ton.B210 cells than in those driven by IL-3. Moreover, nutlin-3 drastically enhanced imatinib-induced apoptosis in a p53-dependent manner in various BCR/ABL-expressing cells, which included primary leukemic cells from patients with CML blast crisis or Ph+ ALL and cells expressing the imatinib-resistant E255K BCR/ABL mutant. Nutlin-3 and imatinib synergistically induced Bax activation, mitochondrial membrane depolarization, and caspase-3 cleavage leading to caspase-dependent apoptosis, which was inhibited by overexpression of Bcl-XL. Imatinib did not significantly affect the nutlin-3-induced expression of p53 but abrogated that of p21. Furthermore, activation of Bax as well as caspase-3 induced by combined treatment with imatinib and nutlin-3 was observed preferentially in cells expressing p21 at reduced levels. The present study indicates that combined treatment with nutlin-3 and imatinib activates p53 without inducing p21 and synergistically activates Bax-mediated intrinsic mitochondrial pathway to induce apoptosis in BCR/ABL-expressing cells. |
| 巻・号 | 15(5) |
| ページ | 608-20 |
| 公開日 | 2010-5-1 |
| DOI | 10.1007/s10495-010-0457-0 |
| PMID | 20094798 |
| MeSH | Animals Apoptosis* / drug effects Apoptosis* / physiology Benzamides Cell Proliferation Cell Survival Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / genetics Fusion Proteins, bcr-abl / genetics Fusion Proteins, bcr-abl / metabolism* Humans Imatinib Mesylate Imidazoles / pharmacology* Interleukin-3 / genetics Interleukin-3 / metabolism K562 Cells / drug effects* Membrane Potential, Mitochondrial / drug effects Mitochondria* / drug effects Mitochondria* / metabolism Piperazines / pharmacology* Protein Kinase Inhibitors / pharmacology* Pyrimidines / pharmacology* bcl-2-Associated X Protein / metabolism |
| IF | 4.543 |
| 引用数 | 29 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 3 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | KU812(RCB0495) K562 |