Abstract
Cell cycle deregulation is a common feature of human cancer. Tumor cells accumulate mutations that result in unscheduled proliferation, genomic instability and chromosomal instability. Several therapeutic strategies have been proposed for targeting the cell division cycle in cancer. Whereas inhibiting the initial phases of the cell cycle is likely to generate viable quiescent cells, targeting mitosis offers several possibilities for killing cancer cells. Microtubule poisons have proved efficacy in the clinic against a broad range of malignancies, and novel targeted strategies are now evaluating the inhibition of critical activities, such as cyclin-dependent kinase 1, Aurora or Polo kinases or spindle kinesins. Abrogation of the mitotic checkpoint or targeting the energetic or proteotoxic stress of aneuploid or chromosomally instable cells may also provide further benefits by inducing lethal levels of instability. Although cancer cells may display different responses to these treatments, recent data suggest that targeting mitotic exit by inhibiting the anaphase-promoting complex generates metaphase cells that invariably die in mitosis. As the efficacy of cell–cycle targeting approaches has been limited so far, further understanding of the molecular pathways modulating mitotic cell death will be required to move forward these new proposals to the clinic.
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Abbreviations
- APC/C:
-
anaphase-promoting complex/cyclosome
- Cdk:
-
cyclin-dependent kinase
- CIN:
-
chromosomal instability
- PARP:
-
poly(ADP-ribose) polymerase
- RNAi:
-
RNA interference
- SAC:
-
spindle assembly checkpoint
- SCF:
-
Skp–Cullin–F-box protein complex
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Acknowledgements
The Cell Division and Cancer group of the CNIO is supported by the Association for International Cancer Research (AICR no. 08-0188), Foundation Ramón Areces, the OncoCycle Programme (S-BIO-0283-2006) from the Comunidad de Madrid, the Spanish Ministry of Science and Innovation (SAF2009-07973 and OncoBIO Consolider-Ingenio 2010 Programme (CSD2007-00017)) and the European Union Seventh Framework Programme (MitoSys project; HEALTH-F5-2010-241548).
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Manchado, E., Guillamot, M. & Malumbres, M. Killing cells by targeting mitosis. Cell Death Differ 19, 369–377 (2012). https://doi.org/10.1038/cdd.2011.197
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DOI: https://doi.org/10.1038/cdd.2011.197
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