Killing cells by targeting mitosis.
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.
Cell Division and Cancer Group, Spanish National Cancer Research Center, Madrid, Spain.
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Manchado
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Guillamot
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Malumbres
D000818:Animals; D064127:Aurora Kinases; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D043171:Chromosomal Instability / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050257:Tubulin Modulators / Q000627:therapeutic use
D047428:Protein Kinase Inhibitors; D050257:Tubulin Modulators; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase