title: A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia.
abstract: The Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Aberrant expression of these kinases occurs in solid tumors and is associated with aneuploidy and carcinogenesis. We found in this study that Aurora kinase A and B were aberrantly expressed in a variety of types of human leukemia cell lines (n = 15, e.g., PALL-1, PALL-2, HL-60, NB4, MV4-11, etc.), as well as freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n = 44) compared with bone marrow mononuclear cells from healthy volunteers (n = 11), as measured by real-time PCR. ZM447439 is a novel selective Aurora kinase inhibitor. The compound induced growth inhibition, caused accumulation of cells with 4N/8N DNA content, and mediated apoptosis of human leukemia cells as measured by thymidine uptake, cell cycle analysis, and annexin V staining, respectively. Especially profound growth inhibition occurred with the PALL-1 and PALL-2 cells, which possess wild-type p53 gene. In contrast, ZM447439 did not inhibit clonogenic growth of myeloid committed stem cells harvested from healthy normal volunteers. Taken together, inhibition of Aurora kinases may be a promising treatment strategy for individuals with leukemia.
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi 783-8505, Japan. ikezoet@kochi-u.ac.jp
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Chie
authors.initials: C
authors.lastname: Nishioka
authors.forename: Taizo
authors.initials: T
authors.lastname: Tasaka
authors.forename: Ayuko
authors.initials: A
authors.lastname: Taniguchi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kuwayama
authors.forename: Naoki
authors.initials: N
authors.lastname: Komatsu
authors.forename: Kentaro
authors.initials: K
authors.lastname: Bandobashi
authors.forename: Kazuto
authors.initials: K
authors.lastname: Togitani
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Hirokuni
authors.initials: H
authors.lastname: Taguchi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001483:Base Sequence; D001549:Benzamides / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D001549:Benzamides; D017931:DNA Primers; D004791:Enzyme Inhibitors; D011799:Quinazolines; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases