Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia
| العنوان: | Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia |
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| المؤلفون: | Quentin Liu, Yi-Xin Zeng, Fei Meng Zheng, Li Hui Wang, Xue Fei Huang, Juan Li, Xian Ren Wang, Xiang Bo Wan, Min Yan, Duo Rong Xu, Shao Kai Luo, Jie Xu |
| المصدر: | Blood. 111:2854-2865 |
| بيانات النشر: | American Society of Hematology, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Adult, G2 Phase, Male, Myeloid, Adolescent, Immunology, Antineoplastic Agents, Apoptosis, Bone Marrow Cells, Protein Serine-Threonine Kinases, Biology, Biochemistry, Piperazines, chemistry.chemical_compound, Aurora kinase, Aurora Kinases, Cell Line, Tumor, hemic and lymphatic diseases, medicine, Humans, Child, VX-680, Mitosis, Aged, Etoposide, bcl-2-Associated X Protein, Kinase, Myeloid leukemia, Drug Synergism, Cell Biology, Hematology, Middle Aged, medicine.disease, Cell biology, Enzyme Activation, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, fms-Like Tyrosine Kinase 3, chemistry, Caspases, Mutation, Cancer research, Female, Drug Screening Assays, Antitumor, Cell Division |
| الوصف: | Previously, we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression ofAur-Awas markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680‐induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML (P < .001) or normal BMMCs (P < .001), suggesting the possible pharmacologic window in targeting Aurora kinase amongAur-A-high VX-680‐ sensitive leukemia patients. VX-680‐ induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G2/M phase arrest, decreased phosphorylated(p)-Akt-1, and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase. Notably, VX-680 increased Bax/ Bcl-2 expression ratio, a favorable proapoptotic predictor for drug response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and that Aur-A-high expression may serve as a differential marker for selective treatment. (Blood. 2008;111: 2854-2865) |
| تدمد: | 1528-0020 0006-4971 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::13ba4b6942c06f7c8795e378700f3c8a https://doi.org/10.1182/blood-2007-07-099325 |
| رقم الأكسشن: | edsair.doi.dedup.....13ba4b6942c06f7c8795e378700f3c8a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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