title: Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia.
abstract: 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.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, 651 Dongfeng Road, Guangzhou, China.
authors.forename: Xue-Fei
authors.initials: XF
authors.lastname: Huang
authors.forename: Shao-Kai
authors.initials: SK
authors.lastname: Luo
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Duo-Rong
authors.initials: DR
authors.lastname: Xu
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Xian-Ren
authors.initials: XR
authors.lastname: Wang
authors.forename: Xiang-Bo
authors.initials: XB
authors.lastname: Wan
authors.forename: Fei-Meng
authors.initials: FM
authors.lastname: Zheng
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D064127:Aurora Kinases; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002648:Child; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D064127:Aurora Kinases; D020169:Caspases; D005047:Etoposide; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D051028:bcl-2-Associated X Protein; D051941:fms-Like Tyrosine Kinase 3; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines