Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia
| Autor: | 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 |
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| Rok vydání: | 2008 |
| Předmět: |
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 |
| Zdroj: | Blood. 111:2854-2865 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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) |
| Databáze: | OpenAIRE |
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