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.

Abstract

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.

• Authors: Jing Yang, Takayuki Ikezoe, Chie Nishioka, Taizo Tasaka, Ayuko Taniguchi, Yoshio Kuwayama, Naoki Komatsu, Kentaro Bandobashi, Kazuto Togitani, H Phillip Koeffler, Hirokuni Taguchi, Akihito Yokoyama
• Journal: Blood (Blood) Vol. 110 Issue 6 Pg. 2034-40 (Sep 15 2007) ISSN: 0006-4971 [Print] United States
• PMID: 17495131 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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
• Antibiotics, Antineoplastic
• Enzyme Inhibitors
• Organophosphates
• Quinazolines
• Tubulin Modulators
• Vincristine
• AURKB protein, human
• Aurka protein, mouse
• Aurkb protein, mouse
• Aurora Kinase A
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases
• Thymidine
• Daunorubicin

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Aurora Kinase A
• Aurora Kinase B
• Aurora Kinases
• Case-Control Studies
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Colony-Forming Units Assay
• Daunorubicin (pharmacology)
• Drug Synergism
• Drug Therapy, Combination
• Drug Tolerance
• Enzyme Inhibitors (pharmacology)
• Female
• Flow Cytometry
• Humans
• Immunoblotting
• Leukemia (drug therapy, enzymology, pathology)
• Mice
• Mice, Inbred BALB C
• Organophosphates (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Quinazolines (pharmacology)
• Thymidine (metabolism)
• Transplantation, Heterologous
• Tubulin Modulators (pharmacology)
• Vincristine (pharmacology)