Synergistic antileukemic effects between ABT-869 and chemotherapy involve downregulation of cell cycle-regulated genes and c-Mos-mediated MAPK pathway
| Autor: | Zhigang Xie, Han Jh, Tai Yc, Michael B. Lilly, Lim Yp, Chonglei Bi, Jianbiao Zhou, Keith B. Glaser, Daniel H. Albert, Chien-Shing Chen, Mengfei Pan, Steven K. Davidsen, Loh Sl |
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| Rok vydání: | 2007 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Indazoles Transplantation Heterologous Down-Regulation Apoptosis Cell Cycle Proteins Mice SCID Biology Receptor tyrosine kinase Mice Downregulation and upregulation hemic and lymphatic diseases Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Doxorubicin RNA Small Interfering Gene Expression Profiling Phenylurea Compounds Cytarabine Receptor Protein-Tyrosine Kinases Myeloid leukemia Drug Synergism Hematology Cell cycle medicine.disease Leukemia Oncology Leukemia Myeloid Acute Disease Proto-Oncogene Proteins c-mos Cancer research biology.protein Drug Therapy Combination Mitogen-Activated Protein Kinases Signal Transduction medicine.drug |
| Zdroj: | Leukemia. 22:138-146 |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | Internal tandem duplications (ITDs) of fms-like tyrosine kinase 3 (FLT3) receptor play an important role in the pathogenesis of acute myeloid leukemia (AML) and represent an attractive therapeutic target. ABT-869 has demonstrated potent effects in AML cells with FLT3-ITDs. Here, we provide further evidence that ABT-869 treatment significantly downregulates cyclins D and E but increases the expression of p21 and p27. ABT-869 induces apoptosis through downregulation of Bcl-xL and upregulation of BAK, BID and BAD. We also evaluate the combinations of ABT-869 and chemotherapy. ABT-869 demonstrates significant sequence-dependent synergism with cytarabine and doxorubicin in cell lines and primary leukemia samples. The optimal combination was validated in MV4-11 xenografts. Low-density array analysis revealed the synergistic interaction involved in downregulation of cell cycle and mitogen-activated protein kinase pathway genes. CCND1 and c-Mos were the most significantly inhibited targets on both transcriptional and translational levels. Treatment with short hairpin RNAs targeting either CCND1 or c-Mos further sensitized MV4-11 cells to ABT-869. These findings suggest that specific pathway genes were further targeted by adding chemotherapy and support the rationale of combination therapy. Thus, a clinical trial using sequence-dependent combination therapy with ABT-869 in AML is warranted. |
| Databáze: | OpenAIRE |
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