Effects of chemical manipulation of mitotic arrest and slippage on cancer cell survival and proliferation

Riffell, Jenna L.; Zimmerman, Carla; Khong, Anthony; McHardy, Lianne M.; Roberge, Michel

doi:10.4161/cc.8.18.9623

Cited by 36 publications

(41 citation statements)

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“…Induction of mitotic slippage by SU6656 and geraldol requires proteasomal activity A previous screening effort by our group identified SU6656 and geraldol as chemicals capable of inducing mitotic slippage (26). When cells spontaneously slip out of mitotic arrest, as well as during normal exit from mitosis, proteasomal activity is required for the degradation of cyclin B1 (24,25).…”

Section: Resultsmentioning

confidence: 99%

“…The cells were exposed to the chemical inducers of mitotic slippage SU6656 (5 mmol/L) or geraldol (5 mmol/L) in the presence of various concentrations of MG-132 for 4 hours and in the continued presence of paclitaxel. Residual unattached mitotic cells were removed and the attached, slipped cells were fixed, stained with Hoechst 33342, and quantified using automated fluorescence microscopy (26). In the absence of MG-132, SU6656 and geraldol induced 60% to 90% of mitotic cells to undergo mitotic slippage.…”

Section: Resultsmentioning

confidence: 99%

“…We previously observed that MCF-7 cells do not undergo mitotic slippage, spontaneous (26) or induced by SU6656 or geraldol (not shown). MCF-7 cells do not express caspase-3 because of a deletion within exon 3 of the CASP-3 gene that results in the introduction of a premature stop codon that completely abrogates translation of the CASP-3 mRNA (37).…”

Section: Su6656 and Geraldol Do Not Induce The Degradation Of Cyclin mentioning

confidence: 99%

“…Individual nuclei of slipped cells were detected and counted using the Cellomics Target Activation Analysis Program. In all figures, mitotic slippage was expressed as a percentage of the cells seeded in each well (26).…”

Section: Slippage Induction Assaymentioning

confidence: 99%

“…Our group and others have identified chemicals that stimulate mitotic slippage and observed that slipped cells typically undergo at least 1 round of DNA replication without subsequent cell division but that, eventually, all cells that undergo mitotic slippage die (26)(27)(28)(29)(30) (27), and fisetin (30); Supplementary Fig. S1].…”

Section: Introductionmentioning

confidence: 99%

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Caspase-3–Dependent Mitotic Checkpoint Inactivation by the Small-Molecule Inducers of Mitotic Slippage SU6656 and Geraldol

Riffell

Jänicke²,

Roberge³

2011

Molecular Cancer Therapeutics

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Microtubule-targeting cancer drugs such as paclitaxel block cell-cycle progression at mitosis by prolonged activation of the mitotic checkpoint. Cells can spontaneously escape mitotic arrest and enter interphase without chromosome segregation by a process termed mitotic slippage that involves the degradation of cyclin B1 without mitotic checkpoint inactivation. Inducing mitotic slippage with chemicals causes cells to die after multiple rounds of DNA replication without cell division, which may enhance the antitumor activity of microtubule-targeting drugs. Here, we explore pathways leading to mitotic slippage by using SU6656 and geraldol, two recently identified chemical inducers of mitotic slippage. Mitotic slippage induced by SU6656 or geraldol was blocked by the proteasome inhibitor MG-132 and involved proteasome-dependent degradation of cyclin B1 and the mitotic checkpoint proteins budding uninhibited by benzimidazole related 1 (BubR1) and cell division cycle 20 (Cdc20) in T98G cells. Mitotic slippage and the degradation of BubR1 and Cdc20 were also inhibited by the caspase-3 and -7 inhibitor DEVD-CHO.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Su6656 and Geraldol Do Not Induce The Degradation Of Cyclin mentioning

confidence: 99%

Section: Slippage Induction Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Caspase-3–Dependent Mitotic Checkpoint Inactivation by the Small-Molecule Inducers of Mitotic Slippage SU6656 and Geraldol

Riffell

Jänicke²,

Roberge³

2011

Molecular Cancer Therapeutics

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Src family kinases maintain the balance between replication stress and the replication checkpoint

Miura

Fukumoto

Morii

et al. 2015

Cell Biology International

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Progression of DNA replication is tightly controlled by replication checkpoints to ensure the accurate and rapid duplication of genetic information. Upon replication stress, the replication checkpoint slows global DNA replication by inhibiting the late-firing origins and by slowing replication fork progression. Activation of the replication checkpoint has been studied in depth; however, little is known about the termination of the replication checkpoint. Here, we show that Src family kinases promote the recovery from replication checkpoints. shRNA knockdown of a Src family kinase, Lyn, and acute chemical inhibition of Src kinases prevented inactivation of Chk1 after removal of replication stress. Consistently, Src inhibition slowed resumption of DNA replication, after the removal of replication blocks. The effect of Src inhibition was not observed in the presence of an ATM/ATR inhibitor caffeine. These data indicate that Src kinases promote the resumption of DNA replication by suppressing ATR-dependent replication checkpoints. Surprisingly, the resumption of replication was delayed by caffeine. In addition, Src inhibition delayed recovery from replication fork collapse. We propose that Src kinases maintain the balance between replication stress and the activity of the replication checkpoint.

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Imaging Flow Cytometry of Multi-Nuclearity

Vorobjev

Bekbayev

Temirgaliyev

et al. 2023

Methods in Molecular Biology

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Multi-nuclearity is a common feature for cells in different cancers. Also, analysis of multi-nuclearity in cultured cells is widely used for evaluating the toxicity of different drugs. Multi-nuclear cells in cancer and under drug treatments form from aberrations in cell division and/or cytokinesis. These cells are a hallmark of cancer progression, and the abundance of multi-nucleated cells often correlates with poor prognosis.The use of standard bright field or fluorescent microscopy to analyze multi-nuclearity at the quantitative level is laborious and can suffer from user bias. Automated slide-scanning microscopy can eliminate scorer bias and improve data collection. However, this method has limitations, such as insufficient visibility of multiple nuclei in the cells attached to the substrate at low magnification.Since quantification of multi-nuclear cells using microscopic methods might be difficult, imaging flow cytometry (IFC) is a method of choice for this. We describe the experimental protocol for the preparation of the samples of multi-nucleated cells from the attached cultures and the algorithm for the analysis of these cells by IFC. Images of multi-nucleated cells obtained after mitotic arrest induced by taxol, as well as cells obtained after cytokinesis blockade by cytochalasin D treatment, can be acquired at a maximal resolution of IFC. We suggest two algorithms for the discrimination of single-nucleus and multi-nucleated cells. The advantages and disadvantages of IFC analysis of multi-nuclear cells in comparison with microscopy are discussed.

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Effects of chemical manipulation of mitotic arrest and slippage on cancer cell survival and proliferation

Cited by 36 publications

References 50 publications

Caspase-3–Dependent Mitotic Checkpoint Inactivation by the Small-Molecule Inducers of Mitotic Slippage SU6656 and Geraldol

Caspase-3–Dependent Mitotic Checkpoint Inactivation by the Small-Molecule Inducers of Mitotic Slippage SU6656 and Geraldol

Src family kinases maintain the balance between replication stress and the replication checkpoint

Imaging Flow Cytometry of Multi-Nuclearity

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