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

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

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

Xue-Fei Huang,Shao-Kai Luo,Jie Xu,Juan Li,Duo-Rong Xu,Li-Hui Wang,Min Yan,Xian-Ren Wang,Xiang-Bo Wan,Fei-Meng Zheng,Yi-Xin Zeng,Quentin Liu,

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, G(2)/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.

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

XF Huang,SK Luo,J Xu,J Li,DR Xu,LH Wang,M Yan,XR Wang,XB Wan,FM Zheng,YX Zeng,Q Liu,

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

PUBLICATION TYPE: Journal Article

Journal: Blood

VOLUME: 111

Page Numbers: 2854-65

Journal Abbreviation: Blood

ISSN: 0006-4971

DAY: 26

MONTH: 12

YEAR: 2007

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

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LANGUAGE: eng

NlmUniqueID: 7603509

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