Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts.
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.


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.
Walsby
Elisabeth
E
Dept. of Haematology, School of Medicine, Cardiff University, Heath Park, Cardiff, South Glamorgan, CF14 4XN, Wales, UK. walsbyej@cf.ac.uk
Walsh
Val
V
Pepper
Chris
C
Burnett
Alan
A
Mills
Ken
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology*; D001752:Blast Crisis; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D010755:Organophosphates / Q000494:pharmacology*; D010766:Phosphorylation; D011003:Ploidies; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
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; C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D006657:Histones; D010755:Organophosphates; D011799:Quinazolines; C531556:AZD 1152-HQPA; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases