Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia

• Published in: Blood 2008-03, Vol.111 (5), p.2854-2865
• Main Authors: Huang, Xue-Fei, Luo, Shao-Kai, Xu, Jie, Li, Juan, Xu, Duo-Rong, Wang, Li-Hui, Yan, Min, Wang, Xian-Ren, Wan, Xiang-Bo, Zheng, Fei-Meng, Zeng, Yi-Xin, Liu, Quentin
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Aurora Kinases; bcl-2-Associated X Protein - metabolism; Biological and medical sciences; Bone Marrow Cells - drug effects; Bone Marrow Cells - enzymology; Bone Marrow Cells - pathology; Caspases - metabolism; Cell Division - drug effects; Cell Line, Tumor; Chemotherapy; Child; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Activation - drug effects; Etoposide - pharmacology; Female; fms-Like Tyrosine Kinase 3 - metabolism; G2 Phase - drug effects; Humans; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - pathology; Male; Medical sciences; Middle Aged; Mutation - genetics; Pharmacology. Drug treatments; Piperazines - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-07-099325

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 of Aur-A was 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 among Aur-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.