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Molecules 2016, 21(5), 663; doi:10.3390/molecules21050663

Antiproliferative Fate of the Tetraploid Formed after Mitotic Slippage and Its Promotion; A Novel Target for Cancer Therapy Based on Microtubule Poisons

1
Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
2
Division of Human Genome Science, Department of Molecular and Cellular Biology, School of Life Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
3
Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Iwao Ojima
Received: 4 April 2016 / Revised: 10 May 2016 / Accepted: 13 May 2016 / Published: 19 May 2016
(This article belongs to the Special Issue New Generation of Microtubule-Interacting Anticancer Agents)
View Full-Text   |   Download PDF [1704 KB, uploaded 19 May 2016]   |  

Abstract

Microtubule poisons inhibit spindle function, leading to activation of spindle assembly checkpoint (SAC) and mitotic arrest. Cell death occurring in prolonged mitosis is the first target of microtubule poisons in cancer therapies. However, even in the presence of microtubule poisons, SAC and mitotic arrest are not permanent, and the surviving cells exit the mitosis without cytokinesis (mitotic slippage), becoming tetraploid. Another target of microtubule poisons-based cancer therapy is antiproliferative fate after mitotic slippage. The ultimate goal of both the microtubule poisons-based cancer therapies involves the induction of a mechanism defined as mitotic catastrophe, which is a bona fide intrinsic oncosuppressive mechanism that senses mitotic failure and responds by driving a cell to an irreversible antiproliferative fate of death or senescence. This mechanism of antiproliferative fate after mitotic slippage is not as well understood. We provide an overview of mitotic catastrophe, and explain new insights underscoring a causal association between basal autophagy levels and antiproliferative fate after mitotic slippage, and propose possible improved strategies. Additionally, we discuss nuclear alterations characterizing the mitotic catastrophe (micronuclei, multinuclei) after mitotic slippage, and a possible new type of nuclear alteration (clustered micronuclei). View Full-Text
Keywords: spindle assembly checkpoint; cell death during mitotic arrest; mitotic slippage; mitotic catastrophe; tetraploid; antiproliferative fate; chemoresistance; basal autophagy; micronuclei; clustered micronuclei spindle assembly checkpoint; cell death during mitotic arrest; mitotic slippage; mitotic catastrophe; tetraploid; antiproliferative fate; chemoresistance; basal autophagy; micronuclei; clustered micronuclei
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Nakayama, Y.; Inoue, T. Antiproliferative Fate of the Tetraploid Formed after Mitotic Slippage and Its Promotion; A Novel Target for Cancer Therapy Based on Microtubule Poisons. Molecules 2016, 21, 663.

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