Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia.
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.
Huang
Xue-Fei
XF
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, 651 Dongfeng Road, Guangzhou, China.
Luo
Shao-Kai
SK
Xu
Jie
J
Li
Juan
J
Xu
Duo-Rong
DR
Wang
Li-Hui
LH
Yan
Min
M
Wang
Xian-Ren
XR
Wan
Xiang-Bo
XB
Zheng
Fei-Meng
FM
Zeng
Yi-Xin
YX
Liu
Quentin
Q
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
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