AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo.
Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. We have recently shown that hematopoietic malignant cells including those from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) aberrantly expressed Aurora A and B kinases, and ZM447439, a potent inhibitor of Aurora kinases, effectively induced growth arrest and apoptosis of a variety of leukemia cells. The present study explored the effect of AZD1152, a highly selective inhibitor of Aurora B kinase, on various types of human leukemia cells. AZD1152 inhibited the proliferation of AML lines (HL-60, NB4, MOLM13), ALL line (PALL-2), biphenotypic leukemia (MV4-11), acute eosinophilic leukemia (EOL-1), and the blast crisis of chronic myeloid leukemia K562 cells with an IC50 ranging from 3 nM to 40 nM, as measured by thymidine uptake on day 2 of culture. These cells had 4N/8N DNA content followed by apoptosis, as measured by cell-cycle analysis and annexin V staining, respectively. Of note, AZD1152 synergistically enhanced the antiproliferative activity of vincristine, a tubulin depolymerizing agent, and daunorubicin, a topoisomerase II inhibitor, against the MOLM13 and PALL-2 cells in vitro. Furthermore, AZD1152 potentiated the action of vincristine and daunorubicin in a MOLM13 murine xenograft model. Taken together, AZD1152 is a promising new agent for treatment of individuals with leukemia. The combined administration of AZD1152 and conventional chemotherapeutic agent to patients with leukemia warrants further investigation.
Yang
Jing
J
Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi, Japan.
Ikezoe
Takayuki
T
Nishioka
Chie
C
Tasaka
Taizo
T
Taniguchi
Ayuko
A
Kuwayama
Yoshio
Y
Komatsu
Naoki
N
Bandobashi
Kentaro
K
Togitani
Kazuto
K
Koeffler
H Phillip
HP
Taguchi
Hirokuni
H
Yokoyama
Akihito
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D016022:Case-Control Studies; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D003630:Daunorubicin / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010755:Organophosphates / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D010755:Organophosphates; D011799:Quinazolines; D050257:Tubulin Modulators; D014750:Vincristine; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D013936:Thymidine; D003630:Daunorubicin