Journal
CANCER LETTERS
Volume 440, Issue -, Pages 64-81Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.10.005
Keywords
Antimitotics; Spindle assembly checkpoint; Mitotic blockers and drivers; Combination therapy; Apoptosis
Categories
Funding
- CESPU - Cooperativa de Ensino Superior Politecnico e Universitario under the project ComeTarget_CESPU_2017
- Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (FCT/MCTES - PIDDAC)
- European Regional Development Fund (ERDF) through the COMPETE - Programa Operacional Factores de Competitividade (POFC) [POCI-01-0145-FEDER-016790, POCI-01-0145-FEDER-007274]
- PPCDT - Promover a Producao Cientifica e Desenvolvimento Tecnologico e a Constituicao de Redes Tematicas [3599, PTDC/MAR-BIO/4694/2014, NORTE-01-0145-FEDER-000012]
- FCT [PTDC/MAR-BIO/4694/2014, SFRH/BD/116167/2016]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/116167/2016] Funding Source: FCT
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Current microtubule-targeting agents (MTAs) remain amongst the most important antimitotic drugs used against a broad range of malignancies. By perturbing spindle assembly, MTAs activate the spindle assembly checkpoint (SAC), which induces mitotic arrest and subsequent apoptosis. However, besides toxic side effects and resistance, mitotic slippage and failure in triggering apoptosis in various cancer cells are limiting factors of MTAs efficacy. Alternative strategies to target mitosis without affecting microtubules have, thus, led to the identification of small molecules, such as those that target spindle Kinesins, Aurora and Polo-like kinases. Unfortunately, these so-called second-generation of antimitotics, encompassing mitotic blockers and mitotic drivers, have failed in clinical trials. Our recent understanding regarding the mechanisms of cell death during a mitotic arrest pointed out apoptosis as the main variable, providing an opportunity to control the cell fates and influence the effectiveness of antimitotics. Here, we provide an overview on the second-generation of antimitotics, and discuss possible strategies that exploit SAC activity, mitotic slippage/exit and apoptosis induction, in order to improve the efficacy of anticancer strategies that target mitosis.
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