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

Yanting Zhu, Yuan Zhou, Jue SHI*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1756-1764
Number of pages9
JournalCell Cycle
Volume13
Issue number11
DOIs
Publication statusPublished - 1 Jun 2014

Scopus Subject Areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

User-Defined Keywords

  • Anti-mitotic drug
  • Apoptosis
  • DNA damage
  • Kinesin-5 inhibitor
  • Mitotic arrest
  • Mitotic slippage
  • Multinucleation
  • Paclitaxel

Fingerprint

Dive into the research topics of 'Post-slippage multinucleation renders cytotoxic variation in anti-mitotic drugs that target the microtubules or mitotic spindle'. Together they form a unique fingerprint.

Cite this