Year-end Sale % OFF 
Abstract
Paclitaxel is a successful anti-cancer drug that kills cancer cells in two-dimensional culture through perturbation of mitosis, but whether it causes tumour regression by anti-mitotic actions is controversial. Drug candidates that specifically target mitosis, including inhibitors of kinesin-5, AurkA, AurkB and Plk1, disappointed in the clinic. Current explanations for this discrepancy include pharmacokinetic differences and hypothetical interphase actions of paclitaxel. Here, we discuss post-mitotic micronucleation as a special activity of taxanes that might explain their higher activity in solid tumours. We review data showing that cells which exit mitosis in paclitaxel are highly micronucleated and suffer post-mitotic DNA damage, and that these effects are much stronger for paclitaxel than kinesin-5 inhibitors. We propose that post-mitotic micronucleation promotes inflammatory signalling via cGAS–STING and other pathways. In tumours, this signalling may recruit cytotoxic leucocytes, damage blood vessels and prime T-cell responses, leading to whole-tumour regression. We discuss experiments that are needed to test the micronucleation hypothesis, and its implications for novel anti-mitotic targets and enhancement of taxane-based therapies.
Highlights
We review data showing that cells which exit mitosis in paclitaxel are highly micronucleated and suffer post-mitotic DNA damage, and that these effects are much stronger for paclitaxel than kinesin-5 inhibitors
We propose that post-mitotic micronucleation promotes inflammatory signalling via cGAS–STING and other pathways
From the early 1990s to the mid-2010s, the mitosis field engaged in a grand experiment, to identify proteins other than tubulin that are essential for mitosis in human cells, develop clinical grade small molecule inhibitors and test them for anti-cancer action in man
Summary
From the early 1990s to the mid-2010s, the mitosis field engaged in a grand experiment, to identify proteins other than tubulin that are essential for mitosis in human cells, develop clinical grade small molecule inhibitors and test them for anti-cancer action in man. Paclitaxel induces dramatic segregation errors, leading to partitioning of the genome into many small nuclei that we term ‘micronucleation’ This effect was noted in early cytological studies of taxane action in two-dimensional culture, at low drug concentrations that do not promote mitotic arrest [7,8]. We revisit it in the light of recent discoveries that micronuclei undergo dramatic DNA damage [9] and nuclear envelope rupture [10], and can activate the pro-inflammatory cGAS–STING pathway [11,12]. We emphasize that our model is speculative, that we respect alternative viewpoints and that more data are needed to decide these complex issues
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
