Journal
OPEN BIOLOGY
Volume 7, Issue 11, Pages -Publisher
ROYAL SOC
DOI: 10.1098/rsob.170182
Keywords
paclitaxel; anti-mitotic; cancer; chemotherapy; kinesin-5; inflammation
Categories
Funding
- NIH-GM
- [NIH-GM39565]
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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 reviewdata 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.
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