Mitosis-targeting therapies: a troubleshooting guide

Doménech, Elena; Malumbres, Marcos

doi:10.1016/j.coph.2013.03.011

Cited by 20 publications

(19 citation statements)

References 101 publications

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“…Due to its critical role in the cell cycle, several Aurora-A inhibitors are currently studied as antitumoral agents (24,25). Because many of these inhibitors can act in a similar way against the three Aurora family members and also be active against other kinases, it is important to discriminate the specific effects of the inhibition of Aurora-A associated with the use of these inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…As this apparent paradox is common to other mitotic regulators, one possibility is that both partial loss-or gain-of-expression induces chromosomal instability and favors tumorigenesis. On the other hand, as all these proteins are required for the cell cycle, their complete depletion impairs cell proliferation, a feature that has been critical for their consideration as putative cancer targets (25,42).…”

Section: Discussionmentioning

confidence: 99%

“…S6), an observation that may explain tumor arrest in the absence of apoptosis or senescence, at least in some specific tissues. Further understanding of these pathways will have important implications in future antitumoral therapies based on the use of inhibitors of Aurora-A or other mitotic targets (25). Given the lack of proper biomarkers for testing the effect of Aurora-A inhibition in clinical trials, a quantification of ploidy or nuclear size in treated tumors could be of help in future assays.…”

Section: Discussionmentioning

confidence: 99%

“…Several small-molecule inhibitors have been shown to block its function, and their in vivo antitumor activity is currently under evaluation in clinical trials for the treatment of human cancer (24). Treatment with Aurora-A inhibitors has resulted in some limited but promising responses in earlyphase clinical trials (25). Improving future trials will require further understanding of the physiologic effects of inhibiting Aurora-A in adult tissues.…”

Section: Introductionmentioning

confidence: 99%

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Requirements for Aurora-A in Tissue Regeneration and Tumor Development in Adult Mammals

et al. 2013

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Aurora-A is a kinase involved in the formation and maturation of the mitotic spindle and chromosome segregation. This kinase is frequently overexpressed in human cancer, and its activity may confer resistance to antitumoral drugs such as Taxol. Inhibition of Aurora-A results in mitotic defects, and this kinase is considered as an attractive therapeutic target for cancer. Nevertheless, the specific requirements for this kinase in adult mammalian tissues remain unclear. Conditional genetic ablation of Aurora-A in adult tissues results in polyploid cells that display a DNA-damage-like response characterized by the upregulation of p53 and the cell-cycle inhibitor p21Cip1 . This is accompanied by apoptotic, differentiation, or senescence markers in a tissue-specific manner. Therapeutic elimination of Aurora-A prevents the progression of skin and mammary gland tumors. However, this is not due to significant levels of apoptosis or senescence, but because Aurora-A-deficient tumors accumulate polyploid cells with limited proliferative potential. Thus, Aurora-A is required for tumor formation in vivo, and the differential response observed in various tissues might have relevant implications in current therapeutic strategies aimed at inhibiting this kinase in the treatment of human cancer. Cancer Res; 73(22); 6804-15. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Requirements for Aurora-A in Tissue Regeneration and Tumor Development in Adult Mammals

et al. 2013

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“…Drugs that interfere with the function of microtubules (such as taxanes) are established, front-line chemotherapeutics but suffer from side-effects and drug resistance 166 .…”

Section: Box 1 | Kinesins and Anticancer Drugsmentioning

confidence: 99%