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Review
, 3 (10), e411

Mitosis-targeted Anti-Cancer Therapies: Where They Stand

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Review

Mitosis-targeted Anti-Cancer Therapies: Where They Stand

K-S Chan et al. Cell Death Dis.

Abstract

The strategy of clinically targeting cancerous cells at their most vulnerable state during mitosis has instigated numerous studies into the mitotic cell death (MCD) pathway. As the hallmark of cancer revolves around cell-cycle deregulation, it is not surprising that antimitotic therapies are effective against the abnormal proliferation of transformed cells. Moreover, these antimitotic drugs are also highly selective and sensitive. Despite the robust rate of discovery and the development of mitosis-selective inhibitors, the unpredictable complexities of the human body's response to these drugs still herald the biggest challenge towards clinical success. Undoubtedly, the need to bridge the gap between promising preclinical trials and effective translational bedside treatment prompts further investigations towards mapping out the mechanistic pathways of MCD, understanding how these drugs work as medicine in the body and more comprehensive target validations. In this review, current antimitotic agents are summarized with particular emphasis on the evaluation of their clinical efficacy as well as their limitations. In addition, we discuss the basis behind the lack of activity of these inhibitors in human trials and the potential and future directions of mitotic anticancer strategies.

Figures

Figure 1
Figure 1
Localization of current druggable protein targets during mitosis (metaphase). The four key subcellular domains highlighted are: (i) mitotic spindle region, (ii) kinetochore/ centromeric region, (iii) centrosomal region and (iv) mitoplasm (nucleoplasm+interphase cytoplasm after the breakdown of the nuclear envelope). It is worth noting that certain proteins exhibit dynamic localization throughout mitosis, such as components of the CPC, which are localized near the centromeres during prophase and metaphase, before shifting to the developing midzone microtubules during anaphase, and finally settled at the midbody during telophase and cytokinesis. Aurora A and Plk1 similarly redistributes to the midbody towards the end stages of mitosis
Figure 2
Figure 2
Interplay of pharmacologic targets in mitosis. A combinatorial anti-mitotic regimen encompassing inhibitors concurrently targeting different stages of mitosis (limiting mitotic entry, strengthening checkpoint arrest and preventing mitotic exit, all of which lead to cell death) may yield higher efficacy in terms of clinical treatment. In addition, such an intense strategy is likely to minimize the development of acquired resistance and/or reduce the drawback of response heterogeneity

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