Cell death response to anti-mitotic drug treatment in cell culture, mouse tumor model and the clinic
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Figure 1
This diagram illustrates anti-mitotic drug responses at the phenotypic level observed by time-lapse microscopy (Gascoigne & Taylor 2008, Orth et al. 2008, Shi et al. 2008, 2011, Zhu et al. 2014). Similar responses are seen with microtubules-targeting drugs, Kinesin-5 inhibitors and Plk1 inhibitors. The timing of events, and the fraction of cells that undergo alternative outcomes, vary between cell lines and drug types. Duration of mitotic arrest varies from 10 to 20 h, and fraction of cells that die from < 5% to 100%. The 4N G1-arrest cells that slip out of mitotic arrest progress to distinct cellular state, likely depending on p53 activity (see text).
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Figure 2
Cell death induced by anti-mitotic drugs during mitotic arrest is mediated by mitochondrial, intrinsic apoptosis triggered by depletion of an anti-apoptotic protein, Mcl-1. The other major negative regulator of mitotic death is Bcl-xL, whose expression level largely determines the sensitivity of different cancer cell lines to anti-mitotics-induced cell death in mitotic arrest.
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Figure 3
Post-slippage cell death induced by anti-mitotic drugs is mediated by mitochondrial, intrinsic apoptosis triggered by DNA damage in the 4N G1-arrest cells. The degree of multinucleation in the post-slippage 4N cells determines the level of DNA damage and subsequent p53-mediated cell death activation. Taxanes engender significantly more mutlinucleation than the spindle-targeting Kinesin-5 inhibitor. Therefore, while different anti-mitotic drugs induce similar degree of cell death during mitotic arrest, the extent of post-slippage death that they trigger vary significantly.
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Figure 4
Variation of apoptotic response to anti-mitotic drugs is much more significant than that of mitotic response between both different mouse tumors and culture human cancer cell lines. (A and B) Fifteen different mouse cancers (propagated by serial passage in mice) were treated with a single dose of paclitaxel. Tumor response was measured as growth delay (x-axis). Mitotic arrest and apoptosis were scored by quantitative histology at different times after drug injection, and peak responses were scored as percentage of cells in the tumor. (A) Plots the average peak mitotic arrest response, and (B) the average peak apoptotic response, against average growth delay for different tumors. Note that most tumors showed a strong mitotic arrest response, but only tumors that respond well to drug show a strong apoptotic response. (A and B) Reproduced, with permission, from Milross et al. (1996). Copyright 1996, Oxford University Press. Comparison of mitotic response (C) and apoptotic response (D) to three different anti-mitotic drugs, including paclitaxel (150 nM, shown in black), nocodazole (500 nM, shown in orange), and Kinesin-5 (Eg5) inhibitor (500 nM, shown in green), for a panel of human cancer cell lines. The mitotic response corresponds to the percentage of mitotic cells after 24 h of drug treatment, probed by phospho-Histone 3 antibody, and the apoptotic response corresponds to the percentage of apoptotic cells after 48 h of drug treatment, probed by Parp1 cleavage. Cell lines are arranged in descending order of sensitivity to anti-mitotics-induced cell death. (C and D) Reproduced, with permission, from Shi et al. (2008). Copyright 2008 AACR.
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Figure 5
This cartoon summarizes the work of the Milas group on the effect of two taxanes on mouse model cancers (Milross et al. 1996, Mason et al. 1997, Schimming et al. 1999). Docetaxel was overall more effective than paclitaxel at the does used, though sensitivity of different tumor lines to the two drugs strongly correlated. In cancers that responded well, docetaxel promoted mainly death in mitosis, and paclitaxel mainly apoptosis after slippage. Death in mitosis following docetaxel treatment was correlated with extensive release of cell debris, including mitotic chromosomes, and massive recruitment of mononuclear leukocytes to the shrinking tumor. Subsequent work suggested that leukocyte recruitment enhances the therapeutic response (Mason et al. 2001). Therefore, timing of cell death may be important in tumors for anti-mitotic response.
- © 2017 Society for Endocrinology
