Post-slippage multinucleation renders cytotoxic variation in anti-mitotic drugs that target the microtubules or mitotic spindle.
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.
Center for Quantitative Systems Biology; Department of Biology and Department of Physics; Hong Kong Baptist University; Hong Kong, China.
Yanting
Y
Zhu
Center for Quantitative Systems Biology; Department of Biology and Department of Physics; Hong Kong Baptist University; Hong Kong, China.
Yuan
Y
Zhou
Center for Quantitative Systems Biology; Department of Biology and Department of Physics; Hong Kong Baptist University; Hong Kong, China.
Jue
J
Shi
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000494:pharmacology*; D034622:RNA Interference; D059010:Single-Cell Analysis / Q000379:methods; D008941:Spindle Apparatus / Q000187:drug effects*; D059008:Time-Lapse Imaging
D000970:Antineoplastic Agents; D015415:Biomarkers; D017239:Paclitaxel
DNA damage; Kinesin-5 inhibitor; anti-mitotic drug; apoptosis; mitotic arrest; mitotic slippage; multinucleation; paclitaxel