Is inflammatory micronucleation the key to a successful anti-mitotic cancer drug?

T. J. Mitchison*, J. Pineda, Jue SHI, S. Florian

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

24 Citations (Scopus)

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.

Original languageEnglish
Article number170182
JournalOpen Biology
Volume7
Issue number11
DOIs
Publication statusPublished - 2017

Scopus Subject Areas

  • Neuroscience(all)
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

User-Defined Keywords

  • Anti-mitotic
  • Cancer
  • Chemotherapy
  • Inflammation
  • Kinesin-5
  • Paclitaxel

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