scholarly journals Conditionally Replicating Adenoviruses Kill Tumor Cells via a Basic Apoptotic Machinery-Independent Mechanism That Resembles Necrosis-Like Programmed Cell Death

2004 ◽  
Vol 78 (22) ◽  
pp. 12243-12251 ◽  
Author(s):  
Mohamed A. I. Abou El Hassan ◽  
Ida van der Meulen-Muileman ◽  
Saman Abbas ◽  
Frank A. E. Kruyt
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Anticancer Agents ◽  
Late Time ◽  
Apoptotic Pathway ◽  
P53 Expression ◽  
Apoptosis Protein ◽  
H460 Cells ◽  
E3 Region

ABSTRACT Conditionally replicating adenoviruses (CRAds) represent a promising class of novel anticancer agents that are used for virotherapy. The E1AΔ24 mutation-based viruses, Ad5-Δ24 [CRAd(E3−); E3 region deleted] and infectivity-enhanced Ad5-Δ24RGD [CRAd(E3+)] have been shown to potently eradicate tumor cells. The presence of the E3 region in the latter virus is known to improve cell killing that can be attributed to the presence of the oncolysis-enhancing Ad death protein. The more precise mechanism by which CRAds kill tumor cells is unclear, and the role of the host cell apoptotic machinery in this process has been addressed only in a limited way. Here, we examine the role of several major apoptotic pathways in the CRAd-induced killing of non-small-cell lung cancer H460 cells. As expected, CRAd(E3+) was more potent than CRAd(E3−). No evidence for the involvement of the p53-Bax apoptotic pathway was found. Western blot analyses demonstrated strong suppression of p53 expression and unchanged Bax levels during viral replication, and stable overexpression of human papillomavirus type 16-E6 in H460 cells did not affect killing by both CRAds. CRAd activity was also not hampered by stable overexpression of anti-apoptotic Bcl2 or BclXL, and endogenous Bcl2/BclXL protein levels remained constant during the oncolytic cycle. Some evidence for caspase processing was obtained at late time points after infection; however, the inhibition of caspases by the X-linked inhibitor of apoptosis protein overexpression or cotreatment with zVAD-fmk did not inhibit CRAd-dependent cell death. Analyses of several apoptotic features revealed no evidence for nuclear fragmentation or DNA laddering, although phosphatidylserine externalization was detected. We conclude that despite the known apoptosis-modulating abilities of individual Ad proteins, Ad5-Δ24-based CRAds trigger necrosis-like cell death. In addition, we propose that deregulated apoptosis in cancer cells, a possible drug resistance mechanism, provides no barrier for CRAd efficacy.

Anticancer Activity of Diosgenin and its Semi-synthetic Derivatives: Role in Autophagy Mediated Cell Death and Induction of Apoptosis

2021 ◽  
Vol 21 ◽  
Author(s):  
Nivedita Bhardwaj ◽  
Nancy Tripathi ◽  
Bharat Goel ◽  
Shreyans K. Jain
Keyword(s):  
Cell Death ◽  
Cancer Treatment ◽  
Anticancer Activity ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Rational Approach ◽  
Potential Candidate ◽  
Potential Implication ◽  
Apoptosis Protein ◽  
Synthetic Derivatives

: During cancer progression, the unrestricted proliferation of cells is supported by the impaired cell death response provoked by certain oncogenes. Both autophagy and apoptosis are the signaling pathways of cell death, which are targeted for cancer treatment. Defects in apoptosis result in reduced cell death and ultimately tumor progression. The tumor cells lacking apoptosis phenomena are killed by ROS- mediated autophagy. The autophagic programmed cell death requires apoptosis protein for inhibiting tumor growth; thus, the interconnection between these two pathways determines the fate of a cell. The cross-regulation of autophagy and apoptosis is an important aspect to modulate autophagy, apoptosis and to sensibilise apoptosis-resistant tumor cells under metabolic stress and might be a rational approach for drug designing strategy for the treatment of cancer. Numerous proteins involved in autophagy have been investigated as the druggable target for anticancer therapy. Several compounds of natural origin have been reported, to control autophagy activity through the PI3K/Akt/mTOR key pathway. Diosgenin, a steroidal sapogenin has emerged as a potential candidate for cancer treatment. It induces ROS-mediated autophagy, inhibits PI3K/Akt/mTOR pathway, and produces cytotoxicity selectively in cancer cells. This review aims to focus on optimal strategies using diosgenin to induce apoptosis by modulating the pathways involved in autophagy regulation and its potential implication in the treatment of various cancer. The discussion has been extended to the medicinal chemistry of semi-synthetic derivatives of diosgenin exhibiting anticancer activity.

The role of mitochondrial apoptotic pathway in islet amyloid-induced β-cell death

2021 ◽  
pp. 111424
Author(s):  
Helen Y. Wong ◽  
Queenie Hui ◽  
Zhenyue Hao ◽  
Garth L. Warnock ◽  
Minna Woo ◽  
...  
Keyword(s):  
Cell Death ◽  
Β Cell ◽  
Islet Amyloid ◽  
Apoptotic Pathway ◽  
Mitochondrial Apoptotic Pathway

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 Mitochondria-Ros Crosstalk in the Control of Cell Death and Aging

2012 ◽  
Vol 2012 ◽  
pp. 1-17 ◽  
Author(s):  
Saverio Marchi ◽  
Carlotta Giorgi ◽  
Jan M. Suski ◽  
Chiara Agnoletto ◽  
Angela Bononi ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Redox State ◽  
Balance Of Power ◽  
Molecular Pathways ◽  
Oxygen Species ◽  
Intrinsic Apoptotic Pathway ◽  
Apoptotic Pathway ◽  
Induce Cell Death

Reactive oxygen species (ROS) are highly reactive molecules, mainly generated inside mitochondria that can oxidize DNA, proteins, and lipids. At physiological levels, ROS function as “redox messengers” in intracellular signalling and regulation, whereas excess ROS induce cell death by promoting the intrinsic apoptotic pathway. Recent work has pointed to a further role of ROS in activation of autophagy and their importance in the regulation of aging. This review will focus on mitochondria as producers and targets of ROS and will summarize different proteins that modulate the redox state of the cell. Moreover, the involvement of ROS and mitochondria in different molecular pathways controlling lifespan will be reported, pointing out the role of ROS as a “balance of power,” directing the cell towards life or death.

scholarly journals Mucin-1 (MUC1) as a promising molecular target in anticancer therapy

2019 ◽  
Vol 73 ◽  
pp. 53-64
Author(s):  
Agnieszka Gornowicz ◽  
Anna Bielawska ◽  
Bożena Popławska ◽  
Krzysztof Bielawski
Keyword(s):  
Tumor Cells ◽  
Anticancer Agents ◽  
Intracellular Signaling ◽  
Current Knowledge ◽  
P53 Protein ◽  
Chemotherapeutic Agents ◽  
Therapeutic Effects ◽  
Mucin 1 ◽  
Shock Proteins

Mucin 1 (MUC1) has been recognized by the National Cancer Institute as one of the most promising molecular targets in cancer therapy. Its overexpression has been demonstrated in many epithelial tumors,especially in breast cancer, whichis associated with poor prognosis. Mucin 1 is an important barrier to the penetration of drugs and takes part in the inhibition of apoptosis in tumor cells. MUC1 triggers the activation of several pathways of intracellular signaling. MUC1 interactions with ICAM-1, E-selectin, galectin-3, EGFR, ERα estrogen receptor, p53 protein, heat shock proteins HSP70 and HSP90 have been demonstrated. The MUC1 membrane subunit contributes to the activation of the ERK1 and ERK2 kinases by the induction of the Ras-Raf-Mek-Erk pathway. In addition, the role of MUC1 in the activation of the WNT/β-catenin/TCF7L2 pathway and the induction of transcription of the cyclin D1 gene was confirmed. Numerous studies have shown that blockade of MUC1 by monoclonal antibodies or small molecule inhibitors may promote therapeutic effects and contribute to increased susceptibility of tumor cells to chemotherapeutic agents. The combined effect of the anti-MUC1 antibody with novel anticancer agents may have a better therapeutic effect than monotherapy. This article reviews the current knowledge about the role of MUC1 in the development and progression of cancer as well as potential novel strategies based on mucin 1 in antineoplastic therapy.

BXQ-350 to target to the lysosome and kill glioblastoma (GBM) cells via activation of apoptotic caspases in vitro.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3639-3639
Author(s):  
Laura Felix ◽  
Timothy J Stephens ◽  
Nikhil J Wilkins
Keyword(s):  
Cell Death ◽  
Cell Line ◽  
Tumor Cells ◽  
Lysosomal Membrane ◽  
Sphingolipid Metabolism ◽  
Activity Levels ◽  
Caspase 9 ◽  
Apoptotic Pathway ◽  
Caspase 7

3639 Background: Apoptosis is a programmed cell death mechanism where cells respond to internal or external stimuli by initiating a cascade of events and enzymes leading to cell death. One of the hallmarks of cancer is the ability of tumor cells to resist these apoptotic stimuli. This allows tumor cells to have aberrant metabolisms, such as sphingolipid metabolism in tumor cell lysosomes, or mutations which would normally commit cells to death. Saposin C, the protein component of BXQ-350, Bexion Pharmaceuticals’ proprietary biotherapeutic, is involved in normal lysosomal sphingolipid metabolism. Removing resistance, shortcutting steps leading to apoptosis, or correcting sphingolipid metabolism can result in the death of these tumor cells. Methods: The GBM cell line Gli36ΔEGFR was plated in 96 well plates at a density of 1x104 cells per well in Dulbecco’s Modified Eagle Media with 10% FBS overnight at 37oC for caspase and cytotoxicity assays. Cells were treated with 9uM to 30uM BXQ-350 in triplicate and incubated for 24 hours at 37oC. Promega’s Caspase-Glo 9 or Caspase-Glo 3/7 reagent was added to appropriate wells and the plates were incubated at room temperature in the dark for 3 hours then luminescence was read. The parallel cytotoxic assay was run under the same conditions except Roche’s MTT labeling reagent was added to the appropriate wells after 24 hours and incubated at 370C for 4 hours. Solubilization solution was added to each well and the plate was incubated at 37oC overnight then absorbance was read. The GBM cell line U87 MG was used to determine lysosomal targeting. U87 MG cells were treated with 10uM BXQ-350 and incubated at 37oC overnight. They were stained with anti-SapC (RFP) and anti-LAMP1 (GFP) antibodies and images were taken. Results: BXQ-350 mediated cell death is correlated with a rise in Caspase 3, Caspase 7 and Caspase 9 activity. The caspase activity levels did not rise until after BXQ-350 passed its IC50 and stayed elevated. Caspases 3/7 levels showed higher activity compared to untreated than Caspase 9. In addition to this, BXQ-350 was seen to colocalize to LAMP1, a lysosomal membrane protein. Conclusions: BXQ-350 tracks to the lysosomal membrane where it initiates the cascade of enzymes necessary to cause apoptosis. Caspases 3/7 are the effector caspases and are necessary for the completion of the apoptotic pathway. The higher activity levels of these caspases show the cells are committed to cell death not allowing these cells to subvert apoptosis. This removes one of the major barriers to fighting cancer.

scholarly journals Redundant role of the cytochrome c-mediated intrinsic apoptotic pathway in pancreatic β-cells

2011 ◽  
Vol 210 (3) ◽  
pp. 285-292 ◽  
Author(s):  
Diana Choi ◽  
Stephanie A Schroer ◽  
Shun Yan Lu ◽  
Erica P Cai ◽  
Zhenyue Hao ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Apoptosis ◽  
Caspase 8 ◽  
Intrinsic Apoptotic Pathway ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Apoptotic Pathway ◽  
Redundant Role

Cytochrome c is one of the central mediators of the mitochondrial or the intrinsic apoptotic pathway. Mice harboring a ‘knock-in’ mutation of cytochrome c, impairing only its apoptotic function, have permitted studies on the essential role of cytochrome c-mediated apoptosis in various tissue homeostasis. To this end, we examined the role of cytochrome c in pancreatic β-cells under homeostatic conditions and in diabetes models, including those induced by streptozotocin (STZ) and c-Myc. Previous studies have shown that both STZ- and c-Myc-induced β-cell apoptosis is mediated through caspase-3 activation; however, the precise mechanism in these modes of cell death was not characterized. The results of our study show that lack of functional cytochrome c does not affect glucose homeostasis or pancreatic β-cell mass under basal conditions. Moreover, the cytochrome c-mediated intrinsic apoptotic pathway is required for neither STZ- nor c-Myc-induced β-cell death. We also observed that the extrinsic apoptotic pathway mediated through caspase-8 was not essential in c-Myc-induced β-cell destruction. These findings suggest that cytochrome c is not required for STZ-induced β-cell apoptosis and, together with the caspase-8-mediated extrinsic pathway, plays a redundant role in c-Myc-induced β-cell apoptosis.

Yuk-Hap-Tang Induces Apoptosis by Intervening Mn-SOD in Human Cervical Carcinoma HeLa Cells

2004 ◽  
Vol 32 (06) ◽  
pp. 883-895 ◽  
Author(s):  
H. J. Chae ◽  
J. M. Park ◽  
G. Y. Lee ◽  
H. R. Park ◽  
S. W. Chae ◽  
...  
Keyword(s):  
Cell Death ◽  
Cervical Carcinoma ◽  
Anticancer Agents ◽  
Hela Cells ◽  
Caspase 3 ◽  
Reduced Glutathione ◽  
Cleavage Product ◽  
P53 Expression ◽  
Human Cervical Carcinoma ◽  
Apoptotic Protein

Yuk-Hap-Tang (YHT) induces cell death in human cervical carcinoma HeLa cells. Caspase-3, -6 and -9 were markedly activated in HeLa cells treated with YHT. The preferred substrate for caspase-3 cysteine protease, PARP, was cleaved to its 85-kDa cleavage product. YHT increased the amount of the anti-apoptotic protein, Bcl-2, and the pro-apoptotic protein, Bax. Although p53 has been reported to accumulate in cancer cells in response to anticancer agents, the p53 expression level was not changed in HeLa cells treated with YHT. Manganese (Mn)-TBAP, a mitochondria-specific SOD mimetic agent and NAC/GSH (N-acetyl cysteine/reduced glutathione) reduced the YHT-induced cytotoxicity and decreased the number of the YHT-induced apoptotic cells. Furthermore, YHT reduced the expression of Mn-SOD protein and its activity in HeLa cells. The data demonstrate that YHT induces the apoptosis of human cervical carcinoma HeLa cells by intervening Mn-SOD.

scholarly journals Human IAP-Like Protein Regulates Programmed Cell Death Downstream of Bcl-xL and Cytochrome c

1998 ◽  
Vol 18 (1) ◽  
pp. 608-615 ◽  
Author(s):  
Colin S. Duckett ◽  
Feng Li ◽  
Yu Wang ◽  
Kevin J. Tomaselli ◽  
Craig B. Thompson ◽  
...  
Keyword(s):  
Cell Death ◽  
Uv Light ◽  
Cysteine Proteases ◽  
Early Event ◽  
Gene Encoding ◽  
Apoptotic Pathway ◽  
Apoptosis Protein ◽  
Caspase Family ◽  
Extracellular Stimuli ◽  
Necrosis Factor

ABSTRACT The gene encoding human IAP-like protein (hILP) is one of several mammalian genes with sequence homology to the baculovirus inhibitor-of-apoptosis protein (iap) genes. Here we show that hILP can block apoptosis induced by a variety of extracellular stimuli, including UV light, chemotoxic drugs, and activation of the tumor necrosis factor and Fas receptors. hILP also protected against cell death induced by members of the caspase family, cysteine proteases which are thought to be the principal effectors of apoptosis. hILP and Bcl-xL were compared for their ability to affect several steps in the apoptotic pathway. Redistribution of cytochromec from mitochondria, an early event in apoptosis, was not blocked by overexpression of hILP but was inhibited by Bcl-xL. In contrast, hILP, but not Bcl-xL, inhibited apoptosis induced by microinjection of cytochromec. These data suggest that while Bcl-xL may control mitochondrial integrity, hILP can function downstream of mitochondrial events to inhibit apoptosis.

Role of sarcolemmal ATP-sensitive potassium channel in oxidative stress-induced apoptosis: mitochondrial connection

2008 ◽  
Vol 294 (3) ◽  
pp. H1317-H1325 ◽  
Author(s):  
Jasna Marinovic ◽  
Marko Ljubkovic ◽  
Anna Stadnicka ◽  
Zeljko J. Bosnjak ◽  
Martin Bienengraeber
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Specific Interaction ◽  
Protective Role ◽  
Apoptotic Cell Death ◽  
Apoptotic Pathway ◽  
Neonatal Cardiomyocytes ◽  
Channel Inhibition

From time of their discovery, sarcolemmal ATP-sensitive K+ (sarcKATP) channels were thought to have an important protective role in the heart during stress whereby channel opening protects the heart from stress-induced Ca2+ overload and resulting damage. In contrast, some recent studies indicate that sarcKATP channel closing can lead to cardiac protection. Also, the role of the sarcKATP channel in apoptotic cell death is unclear. In the present study, the effects of channel inhibition on apoptosis and the specific interaction between the sarcKATP channel and mitochondria were investigated. Apoptotic cell death of cultured HL-1 and neonatal cardiomyocytes following exposure to oxidative stress was significantly increased in the presence of sarcKATP channel inhibitor HMR-1098 as evidenced by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and caspase-3,7 assays. This was paralleled by an increased release of cytochrome c from mitochondria to cytosol, suggesting activation of the mitochondrial death pathway. sarcKATP channel inhibition during stress had no effect on Bcl-2, Bad, and phospho-Bad, indicating that the increase in apoptosis cannot be attributed to these modulators of the apoptotic pathway. However, monitoring of mitochondrial Ca2+ with rhod-2 fluorescent indicator revealed that mitochondrial Ca2+ accumulation during stress is potentiated in the presence of HMR-1098. In conclusion, this study provides novel evidence that opening of sarcKATP channels, through a specific Ca2+-related interaction with mitochondria, plays an important role in preventing cardiomyocyte apoptosis and mitochondrial damage during stress.

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