Key Points
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Human tumour cells are typically aneuploid, with both changes in chromosome number and structure, due to chromosome instability. One source of this instability is mitosis, during which errors in chromosome segregation can lead to gains or losses of chromosomes.
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Members of the Aurora family of protein kinases are required for multiple aspects of mitosis. Aurora-A localizes to centrosomes/spindle poles and is required for spindle assembly, whereas Aurora-B is a chromosome passenger protein required for phosphorylation of histone H3, chromosome segregation and cytokinesis.
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Aurora-A and -B are both overexpressed in a wide range of different human tumours. Aurora-A has also been shown to be an oncogene in in vitro transformation assays.
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Three Aurora-kinase inhibitors have recently been described — ZM447439, Hesperadin and VX-680. All three induce similar phenotypes in cell-based assays and, interestingly, VX-680 shows antitumour activity in rodent xenograft models.
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In mitosis, ZM447439 and Hesperadin both inhibit chromosome alignment and spindle-checkpoint function. RNAi-based experiments and overexpression of Aurora-kinase mutants indicate that these phenotypes seem to be due to inhibition of Aurora-B, not Aurora-A.
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These drugs are not 'antimitotic' agents in that they do not directly inhibit cell-cycle progression. Rather, following an aberrant mitosis, activation of the p53-dependent post-mitotic checkpoint induces 'pseudo G1' cell-cycle arrest.
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Although Aurora-A has received most of the attention so far in terms of a link with human cancer, Aurora-B might be the more suitable anticancer drug target, simply because inhibition of Aurora-B rapidly results in a catastrophic mitosis, which leads to cell death.
Abstract
Errors in mitosis can provide a source of the genomic instability that is typically associated with tumorigenesis. Many mitotic regulators are aberrantly expressed in tumour cells. These proteins could therefore make useful therapeutic targets. The kinases Aurora-A, -B and -C represent a family of such targets and several small-molecule inhibitors have been shown to block their function. Not only have these inhibitors advanced our understanding of mitosis, but, importantly, their in vivo antitumour activity has recently been reported. What have these studies taught us about the therapeutic potential of inhibiting this family of kinases?
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Acknowledgements
We would like to thank S. Green, D. Johnstone, D. Roberts, H. Robson and E. Brown (all from AstraZeneca) for helpful comments on the manuscript. We would also like to thank C. Ditchfield and the AstraZeneca Bioinformatics group for sharing unpublished data.
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Nicholas Keen is an employee of AstraZeneca UK Ltd, part of the AstraZeneca group of companies, and is also a shareholder in the holding company Astrazeneca PLC.
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DATABASES
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FURTHER INFORMATION
Glossary
- MICROTUBULE
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A hollow tube made of α- and β-tubulin subunits, which forms part of the interphase cytoskeleton and the mitotic spindle.
- CHECKPOINT
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A surveillance mechanism that prevents cell-cycle progression in response to events that, if uncorrected, can result in genome damage.
- CENTROSOME
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Microtubule-organizing centre typically found at the centre of the cell and from which the interphase microtubule cytoskeleton radiates. Following duplication in S phase, the two centrosomes form the spindle poles in mitosis.
- SPINDLE CHECKPOINT
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A cell-cycle checkpoint that prevents anaphase until all the chromosomes are correctly bi-oriented on the mitotic-spindle apparatus.
- CYTOKINESIS
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The process of cell division, which is normally coupled to mitosis.
- CHROMOSOME PASSENGER
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A protein that localizes to the chromosomes, and more specifically the centromeres, in the early phases of mitosis, but then relocates to the spindle midzone following anaphase onset.
- ANAPHASE
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Movement of the sister chromatids to opposite spindle poles following loss of sister-chromatid cohesion at the metaphase–anaphase transition.
- CENTROMERE
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A specialized region of the chromosome, typically seen as a primary constriction, which assembles the two kinetochores and maintains sister-chromatid cohesion until the onset of anaphase.
- KINETOCHORE
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Proteinacious structure that assembles at the centromere of each sister chromatid. During mitosis, kinetochores attach and move chromosomes on the microtubule spindle. When unattached, they activate the spindle checkpoint.
- POLYPLOID
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Most normal cells have a 2N (diploid) DNA content. A polyploid cell carries multiple chromosomes, resulting from chromosome replication without nuclear or cell division.
- ENDOREDUPLICATION
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The accumulation of multiple copies of a cell's DNA, which results when replication is not coordinated to the cell cycle.
- PACLITAXEL
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A naturally occurring compound, originally purified from the pacific yew tree, that stabilizes microtubules and has antitumour activity.
- NOCODAZOLE
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A microtubule toxin that prevents microtubule assembly.
- SECOND- OR THIRD-GENERATION INHIBITORS
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Usually describes drugs that were modified from an original class of compounds, using feedback from clinical studies to address any toxicity issues or to optimize biological properties.
- THERAPEUTIC INDEX
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The therapeutic index is a comparison of the amount of a medication that causes the therapeutic effect to the amount that causes toxic effects. A drug with a high therapeutic index produces its therapeutic effects at significantly lower doses than those where limiting toxicology is apparent.
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Keen, N., Taylor, S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 4, 927–936 (2004). https://doi.org/10.1038/nrc1502
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DOI: https://doi.org/10.1038/nrc1502
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