Document Type

Journal Article

Department/Unit

Department of Physics; Department of Biology

Title

Post-slippage multinucleation renders cytotoxic variation in anti-mitotic drugs that target the microtubules or mitotic spindle

Abstract

One common cancer chemotherapeutic strategy is to perturb cell division with anti-mitotic drugs. Paclitaxel, the classic microtubule-targeting anti-mitotic drug, so far still outperforms the newer, more spindle-specific anti-mitotics in the clinic, but the underlying cellular mechanism is poorly understood. In this study we identified post-slippage multinucleation, which triggered extensive DNA damage and apoptosis after drug-induced mitotic slippage, contributes to the extra cytotoxicity of paclitaxel in comparison to the spindle-targeting drug, Kinesin-5 inhibitor. Based on quantitative single-cell microscopy assays, we showed that attenuation of the degree of post-slippage multinucleation significantly reduced DNA damage and apoptosis in response to paclitaxel, and that post-slippage apoptosis was likely mediated by the p53-dependent DNA damage response pathway. Paclitaxel appeared to act as a double-edge sword, capable of killing proliferating cancer cells both during mitotic arrest and after mitotic slippage by inducing DNA damage. Our results thus suggest that to predict drug response to paclitaxel and anti-mitotics in general, 2 distinct sets of bio-markers, which regulate mitotic and post-slippage cytotoxicity, respectively, may need to be considered. Our findings provide important new insight not only for elucidating the cytotoxic mechanisms of paclitaxel, but also for understanding the variable efficacy of different anti-mitotic chemotherapeutics.

Publication Year

2014

Journal Title

Cell Cycle

Volume number

13

Issue number

11

Publisher

Taylor & Francis

First Page (page number)

1756

Last Page (page number)

1764

Referreed

1

Funder

This work was supported by the Hong Kong RGC (#261310) and HKBU (#FRG2/12-13/036) to J.S. EMD534085 was supplied by Merck- Serono.

DOI

10.4161/cc.28672

ISSN (print)

15384101

Link to Publisher’s Edition

http://dx.doi.org/10.4161/cc.28672

Keywords

anti-mitotic drug, mitotic slippage, apoptosis, multinucleation, DNA damage, mitotic arrest, paclitaxel, Kinesin-5 inhibitor

ISSN (electronic)

15514005

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