Document Detail


Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts.
MedLine Citation:
PMID:  18367484     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Aurora kinases play an essential role in the orchestration of chromosome separation and cytokinesis during mitosis. Small-molecule inhibition of the aurora kinases has been shown to result in inhibition of cell division, phosphorylation of histone H3 and the induction of apoptosis in a number of cell systems. These characteristics have led aurora kinase inhibitors to be considered as potential therapeutic agents.
DESIGN AND METHODS: Aurora kinase gene expression profiles were assessed in 101 samples from patients with acute myeloid leukemia. Subsequently, aurora kinase inhibitors were investigated for their in vitro effects on cell viability, histone H3 phosphorylation, cell cycle and morphology in acute myeloid leukemia cell lines and primary acute myeloid leukemia samples.
RESULTS: The aurora kinase inhibitors AZD1152-HQPA and ZM447439 induced growth arrest and the accumulation of hyperploid cells in acute myeloid leukemia cell lines and primary acute myeloid leukemia cultures. Furthermore, both agents inhibited histone H3 phosphorylation and this preceded perturbations in cell cycle and the induction of apoptosis. Single cell cloning assays were performed on diploid and polyploid cells to investigate their colony-forming capacities. Although the polyploid cells showed a reduced capacity for colony formation when compared with their diploid counterparts, they were consistently able to form colonies.
CONCLUSIONS: AZD1152-HQPA- and ZM447439 are effective apoptosis-inducing agents in acute myeloid leukemia cell lines and primary acute myeloid leukemia cultures. However, their propensity to induce polyploidy does not inevitably result in apoptosis.
Authors:
Elisabeth Walsby; Val Walsh; Chris Pepper; Alan Burnett; Ken Mills
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-03-26
Journal Detail:
Title:  Haematologica     Volume:  93     ISSN:  1592-8721     ISO Abbreviation:  Haematologica     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-05-02     Completed Date:  2008-09-24     Revised Date:  2011-07-11    
Medline Journal Info:
Nlm Unique ID:  0417435     Medline TA:  Haematologica     Country:  Italy    
Other Details:
Languages:  eng     Pagination:  662-9     Citation Subset:  IM    
Affiliation:
Dept. of Haematology, School of Medicine, Cardiff University, Heath Park, Cardiff, South Glamorgan, CF14 4XN, Wales, UK. walsbyej@cf.ac.uk
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Apoptosis
Benzamides / pharmacology*
Blast Crisis
Cell Proliferation / drug effects
Enzyme Inhibitors / pharmacology*
Histones / metabolism
Humans
Leukemia, Myeloid, Acute / drug therapy*,  genetics*
Phosphoric Acid Esters / pharmacology*
Phosphorylation
Ploidies
Polyploidy
Protein-Serine-Threonine Kinases / antagonists & inhibitors*
Quinazolines / pharmacology*
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; 0/4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; 0/AZD 1152-HQPA; 0/Antineoplastic Agents; 0/Benzamides; 0/Enzyme Inhibitors; 0/Histones; 0/Phosphoric Acid Esters; 0/Quinazolines; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/aurora kinase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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