scholarly journals Inhibitor of the spindle assembly checkpoint surpasses apoptosis sensitizer in synergy with taxanes

2018 ◽  
Author(s):  
Teng-Long Han ◽  
Zhi-Xin Jiang ◽  
Yun-Tian Li ◽  
Deng-Shan Wu ◽  
Jun Ji ◽  
...  
Keyword(s):  
Cell Death ◽  
Treatment Response ◽  
Tumor Cells ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Slippage ◽  
Induced Apoptosis

AbstractThe antitumor effect of taxanes have been attributed to their ability to induce mitotic arrest through activation of the spindle assembly checkpoint. Cell death following prolonged mitotic arrest is mediated by the intrinsic apoptosis pathway. Thus, apoptosis sensitizers which inhibit antiapoptotic Bcl-2 family proteins has been shown to enhance taxanes-induced cell death. By contrast, spindle checkpoint disruption facilitates mitotic slippage and is thought to promote taxanes resistance. Notably, other modes of cell death also contribute to treatment outcomes. Here we show that inhibition of the spindle checkpoint suppresses taxanes induced apoptosis but increases terminal growth arrest of tumor cells with features of cellular senescence. By using clonogenic assay which measures the net result of multiple forms of cell death and is more reflective of therapeutic response, our finding suggests apoptosis is not a major determinant of antitumor efficacy of taxanes, whereas spindle checkpoint inhibitor displays a long-term advantage over apoptosis sensitizer in blocking colony outgrowth of tumor cells when combined with different microtubule toxins, therefore represents a superior therapeutic strategy.SIGNIFICANCEApoptosis has long been regarded as the primary mechanism of anti-cancer efficacy of taxanes, while the role of the spindle assembly checkpoint (SAC) in treatment response to taxanes has been controversial. Either apoptosis sensitizer or inhibitor of SAC has been reported to synergize with taxanes. While inhibitor of antiapoptotic proteins potentiates taxanes induced apoptosis, inhibitor of SAC suppresses apoptosis by facilitating mitotic slippage, that is why it is implicated in taxanes resistance. By demonstrating that apoptotic rates are not associate with long-term treatment response, not only do we find that inhibitor of SAC displays a long-term advantage over apoptosis sensitizer in combination with taxanes, but we also resolve the dispute around the role of SAC in cellular response to taxanes.

scholarly journals Antagonizing the spindle assembly checkpoint silencing enhances paclitaxel and Navitoclax-mediated apoptosis with distinct mechanistic

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana C. Henriques ◽  
Patrícia M. A. Silva ◽  
Bruno Sarmento ◽  
Hassan Bousbaa
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cell Fate ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Time Lapse ◽  
Antimitotic Drugs ◽  
Mitotic Slippage ◽  
Mitotic Death ◽  
Chronic Activation

AbstractAntimitotic drugs arrest cells in mitosis through chronic activation of the spindle assembly checkpoint (SAC), leading to cell death. However, drug-treated cancer cells can escape death by undergoing mitotic slippage, due to premature mitotic exit. Therefore, overcoming slippage issue is a promising chemotherapeutic strategy to improve the effectiveness of antimitotics. Here, we antagonized SAC silencing by knocking down the MAD2-binding protein p31comet, to delay mitotic slippage, and tracked cancer cells treated with the antimitotic drug paclitaxel, over 3 days live-cell time-lapse analysis. We found that in the absence of p31comet, the duration of mitotic block was increased in cells challenged with nanomolar concentrations of paclitaxel, leading to an additive effects in terms of cell death which was predominantly anticipated during the first mitosis. As accumulation of an apoptotic signal was suggested to prevent mitotic slippage, when we challenged p31comet-depleted mitotic-arrested cells with the apoptosis potentiator Navitoclax (previously called ABT-263), cell fate was shifted to accelerated post-mitotic death. We conclude that inhibition of SAC silencing is critical for enhancing the lethality of antimitotic drugs as well as that of therapeutic apoptosis-inducing small molecules, with distinct mechanisms. The study highlights the potential of p31comet as a target for antimitotic therapies.

scholarly journals Depletion of Survivin suppresses docetaxel-induced apoptosis in HeLa cells by facilitating mitotic slippage

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Teng-Long Han ◽  
Hang Sha ◽  
Jun Ji ◽  
Yun-Tian Li ◽  
Deng-Shan Wu ◽  
...  
Keyword(s):  
Hela Cells ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Clonogenic Survival ◽  
Mitotic Arrest ◽  
Apoptosis Pathway ◽  
Mitotic Slippage ◽  
Intrinsic Apoptosis Pathway ◽  
Apoptosis Protein ◽  
Induced Apoptosis

AbstractThe anticancer effects of taxanes are attributed to the induction of mitotic arrest through activation of the spindle assembly checkpoint. Cell death following extended mitotic arrest is mediated by the intrinsic apoptosis pathway. Accordingly, factors that influence the robustness of mitotic arrest or disrupt the apoptotic machinery confer drug resistance. Survivin is an inhibitor of apoptosis protein. Its overexpression is associated with chemoresistance, and its targeting leads to drug sensitization. However, Survivin also acts specifically in the spindle assembly checkpoint response to taxanes. Hence, the failure of Survivin-depleted cells to arrest in mitosis may lead to taxane resistance. Here we show that Survivin depletion protects HeLa cells against docetaxel-induced apoptosis by facilitating mitotic slippage. However, Survivin depletion does not promote clonogenic survival of tumor cells but increases the level of cellular senescence induced by docetaxel. Moreover, lentiviral overexpression of Survivin does not provide protection against docetaxel or cisplatin treatment, in contrast to the anti-apoptotic Bcl-xL or Bcl-2. Our findings suggest that targeting Survivin may influence the cell response to docetaxel by driving the cells through aberrant mitotic progression, rather than directly sensitizing cells to apoptosis.

scholarly journals Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine

2010 ◽  
Vol 190 (1) ◽  
pp. 73-87 ◽  
Author(s):  
Stefano Santaguida ◽  
Anthony Tighe ◽  
Anna Morena D'Alise ◽  
Stephen S. Taylor ◽  
Andrea Musacchio
Keyword(s):  
Error Correction ◽  
Small Molecule ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
Spindle Assembly ◽  
Dependent Manner ◽  
Crucial Component ◽  
Molecule Inhibitor ◽  
The Relationship

The catalytic activity of the MPS1 kinase is crucial for the spindle assembly checkpoint and for chromosome biorientation on the mitotic spindle. We report that the small molecule reversine is a potent mitotic inhibitor of MPS1. Reversine inhibits the spindle assembly checkpoint in a dose-dependent manner. Its addition to mitotic HeLa cells causes the ejection of Mad1 and the ROD–ZWILCH–ZW10 complex, both of which are important for the spindle checkpoint, from unattached kinetochores. By using reversine, we also demonstrate that MPS1 is required for the correction of improper chromosome–microtubule attachments. We provide evidence that MPS1 acts downstream from the AURORA B kinase, another crucial component of the error correction pathway. Our experiments describe a very useful tool to interfere with MPS1 activity in human cells. They also shed light on the relationship between the error correction pathway and the spindle checkpoint and suggest that these processes are coregulated and are likely to share at least a subset of their catalytic machinery.

Adapt or die: how eukaryotic cells respond to prolonged activation of the spindle assembly checkpoint

2010 ◽  
Vol 38 (6) ◽  
pp. 1645-1649 ◽  
Author(s):  
Valentina Rossio ◽  
Elena Galati ◽  
Simonetta Piatti
Keyword(s):  
Cell Death ◽  
Error Correction ◽  
Mitotic Spindle ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Model System ◽  
Eukaryotic Cells ◽  
Variable Amount ◽  
Mitotic Slippage ◽  
Surveillance Mechanism

Many cancer-treating compounds used in chemotherapies, the so-called antimitotics, target the mitotic spindle. Spindle defects in turn trigger activation of the SAC (spindle assembly checkpoint), a surveillance mechanism that transiently arrests cells in mitosis to provide the time for error correction. When the SAC is satisfied, it is silenced. However, after a variable amount of time, cells escape from the mitotic arrest, even if the SAC is not satisfied, through a process called adaptation or mitotic slippage. Adaptation weakens the killing properties of antimitotics, ultimately giving rise to resistant cancer cells. We summarize here the mechanisms underlying this process and propose a strategy to identify the factors involved using budding yeast as a model system. Inhibition of factors involved in SAC adaptation could have important therapeutic applications by potentiating the ability of antimitotics to cause cell death.

Caspase-8 Determines Chemosensitivity of ALL Cells and Mediates Favorable Interactions of Cytotoxic Drugs,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3511-3511
Author(s):  
Harald Ehrhardt ◽  
Irmela Jeremias
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Epigenetic Silencing ◽  
Cytotoxic Drugs ◽  
Caspase 8 ◽  
Apoptosis Induction ◽  
Drug Induced ◽  
Induced Apoptosis

Abstract Abstract 3511 Sensitivity of tumor cells towards chemotherapy mainly determines the prognosis of patients suffering from acute lymphoblastic leukemia (ALL); nevertheless, underlying mechanisms regulating chemo-sensitivity remain poorly understood. Here, we aimed at characterizing the role of Caspase-8 for chemo-sensitivity of B- and T-ALL cells. Several different drugs of routine anti-leukemia therapy were tested in vitro. All drugs that induced cell death also activated and cleaved Caspase-8. Caspase-8 was activated independently from extrinsic apoptosis signaling suggesting a downstream amplifier role of Caspase-8 upon drug-induced apoptosis in ALL cells. Most importantly, Asparaginase, Cyclophosphamide, Dexamethasone and Doxorubicin induced apoptosis in a Caspase-8 dependent manner as knockdown of Caspase-8 inhibited drug-induced apoptosis. Accordingly in primary ALL cells, the protein expression levels of Caspase-8 correlated with cell death sensitivity towards these cytotoxic drugs in vitro. In contrast, Cytarabin, Etoposid and others induced apoptosis via Caspase-8 independent signaling. Thus protein expression of Caspase-8 should be evaluated as a potential biomarker for risk stratification in ALL. The expression of Caspase-8 is frequently downregulated in tumor cells mostly due to epigenetic silencing by promoter hypermethylation. In previous work, we had shown that Methotrexate is able to upregulate the expression of epigenetically downregulated Caspase-8 which is mediated by the transcription factor p53 (Ehrhardt et al, Oncogene 2008). Here we found that Methotrexate (MTX) was able sensitize B- and T-cell leukemia cell lines for apoptosis induction by the Caspase-8 dependent drugs Asparaginase, Cyclophosphamide, Dexamethasone and Doxorubicin. Sensitization by MTX for drug-induced apoptosis was mediated by p53 and Caspase-8 as shown by stable expression of respective small hairpin RNAs introduced by lentiviral transduction. Accoordingly to the data obtained in cell lines, in patient-derived ALL cells with low expression of Caspase-8, MTX sensitized for induction of apoptosis by Asparaginase, Cyclophosphamide, Dexamethasone and Doxorubicin. Transient transfection of siRNA into patient-derived ALL cells revealed that synergistic apoptosis induction by MTX and these drugs was dependent on p53 and Caspase-8. Our results indicate that Caspase-8 is crucial for the high anti-leukemic efficiency of numerous routine cytotoxic drugs and drug combinations. Re-expression of epigenetically downregulated Caspase-8 represents a promising approach to increase efficiency of anti-leukemic therapy. Retrospectively, our data might explain on a molecular level, why clinical empirical studies already revealed a high anti-leukemic efficiency for some of these drug combinations over decades. Routine, decades-known cytotoxic drugs activate signaling mechanisms recognized rather recently such as reversing epigenetic silencing. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 365
Author(s):  
Carina Colturato-Kido ◽  
Rayssa M. Lopes ◽  
Hyllana C. D. Medeiros ◽  
Claudia A. Costa ◽  
Laura F. L. Prado-Souza ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clinical Problem ◽  
Jurkat Cells ◽  
Leukemia Cells ◽  
Peripheral Mononuclear Blood ◽  
Induced Apoptosis ◽  
Cure Rates

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve the disease outcome. Antipsychotic phenothiazines have emerged as potential candidates to be repositioned as antitumor drugs. It was previously shown that the anti-histaminic phenothiazine derivative promethazine induced autophagy-associated cell death in chronic myeloid leukemia cells, although autophagy can act as a “double-edged sword” contributing to cell survival or cell death. Here we evaluated the role of autophagy in thioridazine (TR)-induced cell death in the human ALL model. TR induced apoptosis in ALL Jurkat cells and it was not cytotoxic to normal peripheral mononuclear blood cells. TR promoted the activation of caspase-8 and -3, which was associated with increased NOXA/MCL-1 ratio and autophagy triggering. AMPK/PI3K/AKT/mTOR and MAPK/ERK pathways are involved in TR-induced cell death. The inhibition of the autophagic process enhanced the cytotoxicity of TR in Jurkat cells, highlighting autophagy as a targetable process for drug development purposes in ALL.

The role of changes in oxidation reduction status within dexamethasone-induced apoptosis in Jurkat tumor cells

2021 ◽  
Vol 172 (10) ◽  
pp. 479-482
Author(s):  
О. L. Nosareva ◽  
◽  
E. A. Stepovaya ◽  
E. V. Shakhristova ◽  
R. M. Karpov ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Oxidation Reduction ◽  
Induced Apoptosis

scholarly journals Epigenetic Targeting of Autophagy via HDAC Inhibition in Tumor Cells: Role of p53

2018 ◽  
Vol 19 (12) ◽  
pp. 3952 ◽  
Author(s):  
Maria Mrakovcic ◽  
Lauren Bohner ◽  
Marcel Hanisch ◽  
Leopold F. Fröhlich
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Histone Deacetylase ◽  
Stress Responses ◽  
Histone Deacetylase Inhibitors ◽  
Tumor Therapy ◽  
Regulatory System ◽  
Anticancer Activities ◽  
Mutational Status

Tumor development and progression is the consequence of genetic as well as epigenetic alterations of the cell. As part of the epigenetic regulatory system, histone acetyltransferases (HATs) and deacetylases (HDACs) drive the modification of histone as well as non-histone proteins. Derailed acetylation-mediated gene expression in cancer due to a delicate imbalance in HDAC expression can be reversed by histone deacetylase inhibitors (HDACi). Histone deacetylase inhibitors have far-reaching anticancer activities that include the induction of cell cycle arrest, the inhibition of angiogenesis, immunomodulatory responses, the inhibition of stress responses, increased generation of oxidative stress, activation of apoptosis, autophagy eliciting cell death, and even the regulation of non-coding RNA expression in malignant tumor cells. However, it remains an ongoing issue how tumor cells determine to respond to HDACi treatment by preferentially undergoing apoptosis or autophagy. In this review, we summarize HDACi-mediated mechanisms of action, particularly with respect to the induction of cell death. There is a keen interest in assessing suitable molecular factors allowing a prognosis of HDACi-mediated treatment. Addressing the results of our recent study, we highlight the role of p53 as a molecular switch driving HDACi-mediated cellular responses towards one of both types of cell death. These findings underline the importance to determine the mutational status of p53 for an effective outcome in HDACi-mediated tumor therapy.

scholarly journals Consequences of mitotic slippage for antimicrotubule drug therapy

2017 ◽  
Vol 24 (9) ◽  
pp. T97-T106 ◽  
Author(s):  
Bing Cheng ◽  
Karen Crasta
Keyword(s):  
Cell Death ◽  
Spindle Assembly Checkpoint ◽  
Mitotic Cell ◽  
G1 Arrest ◽  
Front Line ◽  
Cell Fates ◽  
Mitotic Slippage ◽  
Drug Treatment Outcomes ◽  
Antimicrotubule Agents ◽  
Sustained Activation

Antimicrotubule agents are commonly utilised as front-line therapies against several malignancies, either by themselves or as combination therapies. Cell-based studies have pinpointed the anti-proliferative basis of action to be a consequence of perturbation of microtubule dynamics leading to sustained activation of the spindle assembly checkpoint, prolonged mitotic arrest and mitotic cell death. However, depending on the biological context and cell type, cells may take an alternative route besides mitotic cell death via a process known as mitotic slippage. Here, mitotically arrested cells ‘slip’ to the next interphase without undergoing proper chromosome segregation and cytokinesis. These post-slippage cells in turn have two main cell fates, either cell death or a G1 arrest ensuing in senescence. In this review, we take a look at the factors determining mitotic cell death vs mitotic slippage, post-slippage cell fates and accompanying features, and their consequences for antimicrotubule drug treatment outcomes.

scholarly journals Upstream Regulatory Role for XIAP in Receptor-Mediated Apoptosis

2004 ◽  
Vol 24 (16) ◽  
pp. 7003-7014 ◽  
Author(s):  
John C. Wilkinson ◽  
Enrique Cepero ◽  
Lawrence H. Boise ◽  
Colin S. Duckett
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Death Receptor ◽  
Full Length ◽  
Proliferative Capacity ◽  
Term Survival ◽  
Truncation Mutant ◽  
Short And Long Term ◽  
Induced Apoptosis

ABSTRACT X-linked inhibitor of apoptosis (XIAP) is an endogenous inhibitor of cell death that functions by suppressing caspases 3, 7, and 9. Here we describe the establishment of Jurkat-derived cell lines stably overexpressing either full-length XIAP or a truncation mutant of XIAP that can only inhibit caspase 9. Characterization of these cell lines revealed that following CD95 activation full-length XIAP supported both short- and long-term survival as well as proliferative capacity, in contrast to the truncation mutant but similar to Bcl-xL. Full-length XIAP was also able to inhibit CD95-mediated caspase 3 processing and activation, the mitochondrial release of cytochrome c and Smac/DIABLO, and the loss of mitochondrial membrane potential, whereas the XIAP truncation mutant failed to prevent any of these cell death events. Finally, suppression of XIAP levels by RNA interference sensitized Bcl-xL-overexpressing cells to death receptor-induced apoptosis. These data demonstrate for the first time that full-length XIAP inhibits caspase activation required for mitochondrial amplification of death receptor signals and that, by acting upstream of mitochondrial activation, XIAP supports the long-term proliferative capacity of cells following CD95 stimulation.

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