Mitosis and apoptosis: how is the balance set?

Topham, Caroline; Taylor, Stephen S.

doi:10.1016/j.ceb.2013.07.003

Cited by 159 publications

(184 citation statements)

References 44 publications

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“…Interestingly, the induction of polyploidy by inhibitors of mitosis is associated with drug resistance, 23,46 and it has been proposed that the continued survival of polyploid cells may give rise to aneuploidy that promotes cancer progression. 46,[53][54][55][56] Deng et al measured vincristine sensitivity in DLBCL cell lines and found that SUDHL8 cells were relatively resistant while SUDHL4 cells were much more sensitive. 57 We found that exposure to belinostat largely prevents the vincristine-induced accumulation of polyploid SUDHL8 cells by triggering apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Cancer cells exposed to different classes of mitosis-targeting drugs, including MTAs, respond in 2 main ways to a prolonged mitotic arrest, either dying during mitosis or undergoing mitotic slippage dependent on the cell line or the drug [reviewed in 53 ]. After mitotic slippage, cells have been shown to enter G1 in a tetraploid state after which they may become senescent, die by apoptosis, or progress through the cell cycle, all by mechanisms that are poorly understood [reviewed in 54 ].…”

Section: Discussionmentioning

confidence: 99%

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Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Havas

Rodrigues

Bhakta

et al. 2016

Cancer Biology & Therapy

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Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with a variety of other drugs. However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, celltype specific mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines. In the current study, we demonstrate that cell lines sensitive to the cytotoxic effects of HDACi undergo early mitotic arrest prior to apoptosis. In contrast, HDACi-resistant cell lines complete mitosis after a short delay and arrest in G1. To force mitotic arrest in HDACi-resistant cell lines, we used low dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity. Belinostat curtails vincristine-induced mitotic arrest and triggers a strong apoptotic response associated with downregulated MCL-1 expression and upregulated BIM expression. Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression. Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population. Our study demonstrates that vincristine sensitizes DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevents polyploidy that could cause vincristine resistance. Our findings provide a rationale for using low dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Havas

Rodrigues

Bhakta

et al. 2016

Cancer Biology & Therapy

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“…The use of Cyt‐B limits scoring of MN to once‐divided BN cells and avoids the scoring of spurious MN that may appear from a number of confounding factors such as less than optimal cell culture conditions and altered cell division kinetics 5. However, it has been demonstrated that noncytokinesis‐blocked versions of the assay can identify statistically significant increases in MN among aneugens which arise from the phenomenon of mitotic slippage 6, 7, 8. Therefore, it is often necessary to perform the assay both in the presence and absence of Cyt‐B, which increases the number of samples that must be evaluated.…”

Section: Introductionmentioning

confidence: 99%

Automation of the in vitro micronucleus assay using the Imagestream^® imaging flow cytometer

Rodrigues¹

2018

Cytometry Pt A

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The in vitro micronucleus (MN) assay is a well‐established test for evaluating genotoxicity and cytotoxicity. The use of manual microscopy to perform the assay can be laborious and often suffers from user subjectivity and interscorer variability. Automated methods including slide‐scanning microscopy and conventional flow cytometry have been developed to eliminate scorer bias and improve throughput. However, these methods possess several limitations such as lack of cytoplasmic visualization using slide‐scanning microscopy and the inability to visually confirm the legitimacy of MN or storage of image data for re‐evaluation using flow cytometry. The ImageStreamX® MK II (ISX) imaging flow cytometer has been demonstrated to overcome all of these limitations. The ISX combines the speed, statistical robustness, and rare event capture capability of conventional flow cytometry with high resolution fluorescent imagery of microscopy and possesses the ability to store all collected image data. This paper details the methodology developed to perform the in vitro MN assay in human lymphoblastoid TK6 cells on the ISX. High resolution images of micronucleated mono‐ and bi‐nucleated cells as well as polynucleated cells can be acquired at a high rate of capture. All images can then be automatically identified, categorized and enumerated in the data analysis software that accompanies the ImageStream, allowing for the scoring of both genotoxicity and cytotoxicity. The results demonstrate that statistically significant increases in MN frequency when compared with solvent controls can be detected at varying levels of cytotoxicity following exposure to well‐known aneugens and clastogens. This work demonstrates a fully automated method for performing the in vitro micronucleus assay on the ISX imaging flow cytometry platform. © 2018 The Author. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.

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“…[1][2][3][4] Apoptosis is a physiological mode of cell death that permits the removal of unwanted cells from the body at a specific time or in response to a given signal. All the molecular components cells need to carry out this cell death process are present in normal healthy cells, and require only activation for apoptosis to ensue.…”

mentioning

confidence: 99%

T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

et al. 2015

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We developed a model system to investigate apoptotic resistance in T cells using osmotic stress (OS) to drive selection of deathresistant cells. Exposure of S49 (Neo) T cells to multiple rounds of OS followed by recovery of surviving cells resulted in the selection of a population of T cells (S49 ) that failed to die in response to a variety of intrinsic apoptotic stimuli including acute OS, but remained sensitive to extrinsic apoptotic initiators. Genome-wide microarray analysis comparing the S49 (OS 4-25) with the parent S49 (Neo) cells revealed over 8500 differentially regulated genes, with almost 90% of those identified being repressed. Surprisingly, our data revealed that apoptotic resistance is not associated with expected changes in pro-or antiapoptotic Bcl-2 family member genes. Rather, these cells lack several characteristics associated with the initial signaling or activation of the intrinsic apoptosis pathway, including failure to increase mitochondrial-derived reactive oxygen species, failure to increase intracellular calcium, failure to deplete glutathione, failure to release cytochrome c from the mitochondria, along with a lack of induced caspase activity. The S49 (OS 4-25) cells exhibit metabolic characteristics indicative of the Warburg effect, and, despite numerous changes in mitochondria gene expression, the mitochondria have a normal metabolic capacity. Interestingly, the S49 (OS 4-25) cells have developed a complete dependence on glucose for survival, and glucose withdrawal results in cell death with many of the essential characteristics of apoptosis. Furthermore, we show that other dietary sugars such as galactose support the viability of the S49 (OS 4-25) cells in the absence of glucose; however, this carbon source sensitizes these cells to die. Our findings suggest that carbon substrate reprogramming for energy production in the S49 (OS 4-25) cells results in stimulusspecific recognition defects in the activation of intrinsic apoptotic pathways.

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Mitosis and apoptosis: how is the balance set?

Cited by 159 publications

References 44 publications

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Automation of the in vitro micronucleus assay using the Imagestream^® imaging flow cytometer

T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

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Mitosis and apoptosis: how is the balance set?

Cited by 159 publications

References 44 publications

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Automation of the in vitro micronucleus assay using the Imagestream® imaging flow cytometer

T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

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Automation of the in vitro micronucleus assay using the Imagestream^® imaging flow cytometer