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Cited by 79Microtubule and mitosis dynamicsCell death mechanisms and regulationCancer Treatment and Pharmacology

Cell death response to anti-mitotic drug treatment in cell culture, mouse tumor model and the clinic

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Shi, Jue, Mitchison, Timothy J·2017·Endocrine-Related Cancer
DOI 10.1530/erc-17-0003PMC PMC5557680
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Abstract

Anti-mitotic cancer drugs include classic microtubule-targeting drugs, such as taxanes and vinca alkaloids, and the newer spindle-targeting drugs, such as inhibitors of the motor protein; Kinesin-5 (aka KSP, Eg5, KIF11); and Aurora-A, Aurora-B and Polo-like kinases. Microtubule-targeting drugs are among the first line of chemotherapies for a wide spectrum of cancers, but patient responses vary greatly. We still lack understanding of how these drugs achieve a favorable therapeutic index, and why individual patient responses vary. Spindle-targeting drugs have so far shown disappointing results in the clinic, but it is possible that certain patients could benefit if we understand their mechanism of action better. Pre-clinical data from both cell culture and mouse tumor models showed that the cell death response is the most variable point of the drug action. Hence, in this review we focus on current mechanistic understanding of the cell death response to anti-mitotics. We first draw on extensive results from cell culture studies, and then cross-examine them with the more limited data from animal tumor models and the clinic. We end by discussing how cell type variation in cell death response might be harnessed to improve anti-mitotic chemotherapy by better patient stratification, new drug combinations and identification of novel targets for drug development.

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  • The interphase effects of microtubule-targeting agents probably contribute to their clinical efficacy.

    “Although the perturbation of mitosis has long been regarded as the explanation for the anti-tumour effects of MTAs, drugs specifically targeting the formation of the mitotic spindle, such as kinesin-5 inhibitors, have shown disappointing results in the clinic, suggesting that the interphase effects of MTAs probably contribute to their clinical efficacy 11,12 .”

    From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [12]

    The section “Clinical responses to microtubule-targeting vs. spindle-targeting anti-mitotic drugs” reports disappointing clinical results for spindle-targeting drugs and proposes interphase effects as one possible explanation. It says those effects may contribute to the effects of taxanes and vincas on solid tumors, but also offers an alternative explanation; it does not establish that interphase effects probably contribute to clinical efficacy. (LLM, conf=0.85)

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References 93 · Cited by 79

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Authors
Shi, J., & Mitchison, T. J.
Affiliations
  • Hong Kong Baptist University (HK)
  • Harvard University (US)
Corresponding author
Shi, Jue
ORCID
Venue
Endocrine-Related Cancer
Publisher
Bioscientifica
Published
2017-09
Volume
24
Issue
9
Pages
T83-T96
ISSN
  • 1351-0088 (ISSN-L)
  • 1479-6821
DOI
10.1530/erc-17-0003
PMC
PMC5557680
OpenAlex
W2592682092
Cited by
79
References
93
Citations by year
2026: 7 · 2025: 7 · 2024: 2 · 2023: 11 · 2022: 7 · 2021: 12 · 2020: 12 · 2019: 9 · 2018: 7 · 2017: 5
FWCI
1.08
Type
journal article
Language
en
Open access
Locations
  • Endocrine Related Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HKBU Institutional Repository (Hong Kong Baptist University) (submittedVersion)
Funders
National Cancer Institute (CA139980, P01CA078048, P01CA139980, CA078048)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
Keywords
antimitotic agents, cell death, microtubule inhibitors, taxanes, vinca alkaloids, Eg5, Aurora kinases, Polo-like kinase, patient stratification, combination therapy, therapeutic index, mouse tumor model
MeSH terms
Animals, Disease Models, Animal, DNA Damage, Humans, Microtubules, Spindle Apparatus, Neoplasms, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Cell Death, Antimitotic Agents, Mice

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