571 Molecular events during cold stress induced cell-death on multidrug resistant leukemic cells

Abstract Caspase-independent programmed cell death can exhibit either an apoptosis-like or a necrosis-like morphology. The ABL kinase inhibitor, imatinib mesylate, has been reported to induce apoptosis of BCR-ABL–positive cells in a caspase-dependent fashion. We investigated whether caspases alone were the mediators of imatinib mesylate–induced cell death. In contrast to previous reports, we found that a broad caspase inhibitor, zVAD-fmk, failed to prevent the death of imatinib mesylate–treated BCR-ABL–positive human leukemic cells. Moreover, zVAD-fmk–preincubated, imatinib mesylate–treated cells exhibited a necrosis-like morphology characterized by cellular pyknosis, cytoplasmic vacuolization, and the absence of nuclear signs of apoptosis. These cells manifested a loss of the mitochondrial transmembrane potential, indicating the mitochondrial involvement in this caspase-independent necrosis. We excluded the participation of several mitochondrial factors possibly involved in caspase-independent cell death such as apoptosis-inducing factor, endonuclease G, and reactive oxygen species. However, we observed the mitochondrial release of the serine protease Omi/HtrA2 into the cytosol of the cells treated with imatinib mesylate or zVAD-fmk plus imatinib mesylate. Furthermore, serine protease inhibitors prevented the caspase-independent necrosis. Taken together, our results suggest that imatinib mesylate induces a caspase-independent, necrosis-like programmed cell death mediated by the serine protease activity of Omi/HtrA2.

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Protein synthesis persists during necrotic cell death

The Journal of Cell Biology ◽

10.1083/jcb.200407162 ◽

2005 ◽

Vol 168 (4) ◽

pp. 545-551 ◽

Cited By ~ 49

Author(s):

Xavier Saelens ◽

Nele Festjens ◽

Eef Parthoens ◽

Isabel Vanoverberghe ◽

Michael Kalai ◽

...

Keyword(s):

Cell Death ◽

Protein Synthesis ◽

De Novo ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Necrotic Cell Death ◽

Necrotic Cell ◽

Proteolytic Activation ◽

Double Stranded Rna ◽

Molecular Events

Cell death is an intrinsic part of metazoan development and mammalian immune regulation. Whereas the molecular events orchestrating apoptosis have been characterized extensively, little is known about the biochemistry of necrotic cell death. Here, we show that, in contrast to apoptosis, the induction of necrosis does not lead to the shut down of protein synthesis. The rapid drop in protein synthesis observed in apoptosis correlates with caspase-dependent breakdown of eukaryotic translation initiation factor (eIF) 4G, activation of the double-stranded RNA-activated protein kinase PKR, and phosphorylation of its substrate eIF2-α. In necrosis induced by tumor necrosis factor, double-stranded RNA, or viral infection, de novo protein synthesis persists and 28S ribosomal RNA fragmentation, eIF2-α phosphorylation, and proteolytic activation of PKR are absent. Collectively, these results show that, in contrast to apoptotic cells, necrotic dying cells retain the opportunity to synthesize proteins.

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Nanomaterials combine multiple therapeutic approaches for cancer cell multidrug resistance, ferroptotic cell death is promising in various cancers

10.31219/osf.io/7bg9t ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Cell Death ◽

Multidrug Resistance ◽

Cancer Cell ◽

High Efficiency ◽

New Technologies ◽

Multidrug Resistant ◽

Therapeutic Approaches ◽

Combination Strategies ◽

New Strategy ◽

Chemotherapy Patients

Cancer cell multidrug resistance (MDR) is one of the most significant barriers to chemotherapy patients' ability to treat malignant tumors.This review first discusses the basic processes of MDR and then details the newest usage of nanomaterials combining multiple therapeutic approaches (e.g. PDT, PTT, gas therapy, gene therapy, and CDT) with MDR chemotherapy. We also analyze the advantages and rationales of these combination systems and why they can reduce MDR cancer cells. Currently, together with various new treatment approaches, MDR-related chemotherapeutic research is gaining momentum in search of better therapeutic results. PDT, for example, has the ability to eliminate high-efficiency multidrug-resistant malignancies but has limited relevance to tumor treatment. In this perspective, SDT is a highly promising approach as it increases ROS production utilizing ultrasonic vibrations, allowing magnitude orders to reach deeper than light. PTT is also often criticized for NIR light's restricted penetration depth; thermomagnetic therapy, using magnetic fields to produce local tissue hyperthermia, can considerably alleviate this problem. However, current research on the possibilities of using these new technologies to fight MDR remains rather rare, and more combination strategies should be carefully investigated in the future. Moreover, ongoing discoveries of cell death pathways, highlighted by recent ferroptosis findings, present a new strategy for our battle against MDR and may revolutionize our knowledge of MDR formation. Ferroptotic cell death promises to treat MDR in various cancers. While most of this cutting-edge research is still in its infancy, we anticipate gaining a deeper understanding of the effectiveness of these revolutionary anti-MDR medicines in the near future.

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Insertion of the βGeo Promoter Trap into the Fem1c Gene of ROSA3 Mice

Molecular and Cellular Biology ◽

10.1128/mcb.24.9.3794-3803.2004 ◽

2004 ◽

Vol 24 (9) ◽

pp. 3794-3803 ◽

Cited By ~ 6

Author(s):

Cassandra L. Schlamp ◽

Andrew T. Thliveris ◽

Yan Li ◽

Louis P. Kohl ◽

Claudia Knop ◽

...

Keyword(s):

Cell Death ◽

Ganglion Cells ◽

Neuronal Cell Death ◽

Insertion Site ◽

Neuronal Cell ◽

Pyramidal Cells ◽

Coding Region ◽

Protein Levels ◽

Molecular Events ◽

Promoter Trap

ABSTRACT ROSA3 mice were developed by retroviral insertion of the βGeo gene trap vector. Adult ROSA3 mice exhibit widespread expression of the trap gene in epithelial cells found in most organs. In the central nervous system the highest expression of βGeo is found in CA1 pyramidal cells of the hippocampus, Purkinje cells of the cerebellum, and ganglion cells of the retina. Characterization of the genomic insertion site for βGeo in ROSA3 mice shows that the trap vector is located in the first intron of Fem1c, a gene homologous to the sex-determining gene fem-1 of Caenorhabditis elegans. Transcription of the Rosa3 allele (R3) yields a spliced message that includes the first exon of Fem1c and the βGeo coding region. Although normal processing of the Fem1c transcript is disrupted in homozygous Rosa3 (Fem1cR3/R3 ) mice, some tissues show low levels of a partially processed transcript containing exons 2 and 3. Since the entire coding region of Fem1c is located in these two exons, Fem1cR3/R3 mice may still be able to express a putative FEM1C protein. To this extent, Fem1cR3/R3 mice show no adverse effects in their sexual development or fertility or in the attenuation of neuronal cell death, another function that has been attributed to both fem-1 and a second mouse homolog, Fem1b. Examination of βGeo expression in ganglion cells after exposure to damaging stimuli indicates that protein levels are rapidly depleted prior to cell death, making the βGeo reporter gene a potentially useful marker to study early molecular events in damaged neurons.

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Modulation of rhodamine 123 uptake by nigericin in sensitive and multidrug resistant leukemic cells

Cancer Letters ◽

10.1016/0304-3835(94)90360-3 ◽

1994 ◽

Vol 84 (1) ◽

pp. 75-83 ◽

Cited By ~ 4

Author(s):

Yvan Canitrot ◽

Dominique Lautier ◽

Pierre Viallet ◽

Jean-Marie Salmon

Keyword(s):

Multidrug Resistant ◽

Leukemic Cells ◽

Rhodamine 123

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Molecular Events Involved in Influenza A Virus-Induced Cell Death

Frontiers in Microbiology ◽

10.3389/fmicb.2021.797789 ◽

2022 ◽

Vol 12 ◽

Author(s):

Rui Gui ◽

Quanjiao Chen

Keyword(s):

Cell Death ◽

Influenza A Virus ◽

Influenza A ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Tissue Destruction ◽

Inflammatory Reactions ◽

Molecular Events ◽

Host Death

Viral infection usually leads to cell death. Moderate cell death is a protective innate immune response. By contrast, excessive, uncontrolled cell death causes tissue destruction, cytokine storm, or even host death. Thus, the struggle between the host and virus determines whether the host survives. Influenza A virus (IAV) infection in humans can lead to unbridled hyper-inflammatory reactions and cause serious illnesses and even death. A full understanding of the molecular mechanisms and regulatory networks through which IAVs induce cell death could facilitate the development of more effective antiviral treatments. In this review, we discuss current progress in research on cell death induced by IAV infection and evaluate the role of cell death in IAV replication and disease prognosis.

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2',3'-Dideoxyadenosine is selectively toxic for TdT-positive cells

Blood ◽

10.1182/blood.v71.6.1601.bloodjournal7161601 ◽

1988 ◽

Vol 71 (6) ◽

pp. 1601-1608

Author(s):

Z Spigelman ◽

R Duff ◽

GP Beardsley ◽

S Broder ◽

D Cooney ◽

...

Keyword(s):

Cell Death ◽

Cell Lines ◽

Ex Vivo ◽

Exposure Period ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Terminal Deoxynucleotidyl Transferase ◽

Parental Line ◽

Continuous Exposure ◽

Hiv Replication

The 2′,3′-dideoxynucleosides (ddNs) are currently undergoing clinical evaluation as antiretroviral agents in HIV-infected individuals. When phosphorylated, the ddNs (ddNTPs) function as chain-terminating substrate analogues with reverse transcriptase, thereby inhibiting HIV replication. These nucleoside analogues can also inhibit, by chain- terminating additions, the primitive lymphoid DNA polymerase, terminal deoxynucleotidyl transferase (TdT). To determine the effect of possible intracellular chain-terminating additions of ddNMPs by TdT, we exposed a series of TdT-positive and TdT-negative cell lines to 2′,3′- dideoxyadenosine (ddA), a representative ddN. At ddA concentrations 25- fold higher than required for inhibition of HIV replication, progressive dose-related cytotoxicity was observed in the TdT-positive cell lines. This was accentuated by the adenosine deaminase inhibitor Coformycin (CF), presumably by enhancing the intracellular generation of ddATP from ddA. A central role of TdT in mediating the ddA/CF cytotoxicity was suggested by studies in a pre-B-cell line rendered TdT positive by infection with a TdT cDNA-containing retroviral vector. After a 48-hour continuous exposure period to 250 mumol/L ddA and 30 mumol/L CF, 30% cell death was observed in the TdT-negative parental line, whereas 90% cell death was observed in the TdT-positive daughter line. Exposure of fresh TdT-positive leukemic cells to ddA/CF for 72 hours ex vivo resulted in cytotoxicity (six cases of acute lymphocytic leukemia [ALL]) while not affecting TdT-negative acute leukemic cells (six cases). We conclude that ddA/CF selectively damages TdT-positive cells, presumably by chain-terminating additions of ddAMP, and that this may have therapeutic relevance in TdT-positive malignant disease.

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High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy

Blood ◽

10.1182/blood.v81.11.3091.bloodjournal81113091 ◽

1993 ◽

Vol 81 (11) ◽

pp. 3091-3096 ◽

Cited By ~ 8

Author(s):

L Campos ◽

JP Rouault ◽

O Sabido ◽

P Oriol ◽

N Roubi ◽

...

Keyword(s):

Cell Death ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Mitochondrial Protein ◽

High Expression ◽

Leukemic Cells ◽

Stem Cell Marker ◽

Cell Counts ◽

Response To Chemotherapy ◽

Acute Myeloid

The BCL-2 proto-oncogene encodes a mitochondrial protein that blocks programmed cell death. High amounts of bcl-2 protein are found not only in lymphoid malignancies, but also in normal tissues characterized by apoptotic cell death, including bone marrow. Using a monoclonal antibody to bcl-2 protein, we analyzed 82 samples of newly diagnosed acute myeloid leukemia. The number of bcl-2+ cells in each sample was heterogeneous (range, 0% to 95%), with a mean of 23%. The percentage of bcl-2+ cells was higher in M4 and M5 types, according to French- American-British classification, and in cases with high white blood cell counts. bcl-2 expression was also correlated with that of the stem cell marker CD34. In vitro survival of leukemic cells maintained in liquid culture in the absence of growth factors was significantly longer in cases with a high percentage of bcl-2+ cells. High expression of bcl-2 was associated with a low complete remission rate after intensive chemotherapy (29% in cases with 20% or more positive cells v 85% in cases with less than 20% positive cells, P < 10(-5)) and with a significantly shorter survival. In multivariate analysis, the percentage of bcl-2+ cells (or the blast survival in culture), age, and the percentage of CD34+ cells were independently associated with poor survival.

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E4F1 deficiency results in oxidative stress–mediated cell death of leukemic cells

Journal of Experimental Medicine ◽

10.1084/jem.20101995 ◽

2011 ◽

Vol 208 (7) ◽

pp. 1403-1417 ◽

Cited By ~ 15

Author(s):

Elodie Hatchi ◽

Genevieve Rodier ◽

Matthieu Lacroix ◽

Julie Caramel ◽

Olivier Kirsh ◽

...

Keyword(s):

Cell Death ◽

Cell Lines ◽

Myeloid Leukemia ◽

Tumor Regression ◽

Fetal Liver ◽

Leukemia Cell ◽

Leukemic Cells ◽

Viral Oncoprotein ◽

Mitochondrial Defects

The multifunctional E4F1 protein was originally discovered as a target of the E1A viral oncoprotein. Growing evidence indicates that E4F1 is involved in key signaling pathways commonly deregulated during cell transformation. In this study, we investigate the influence of E4F1 on tumorigenesis. Wild-type mice injected with fetal liver cells from mice lacking CDKN2A, the gene encoding Ink4a/Arf, developed histiocytic sarcomas (HSs), a tumor originating from the monocytic/macrophagic lineage. Cre-mediated deletion of E4F1 resulted in the death of HS cells and tumor regression in vivo and extended the lifespan of recipient animals. In murine and human HS cell lines, E4F1 inactivation resulted in mitochondrial defects and increased production of reactive oxygen species (ROS) that triggered massive cell death. Notably, these defects of E4F1 depletion were observed in HS cells but not healthy primary macrophages. Short hairpin RNA–mediated depletion of E4F1 induced mitochondrial defects and ROS-mediated death in several human myeloid leukemia cell lines. E4F1 protein is overexpressed in a large subset of human acute myeloid leukemia samples. Together, these data reveal a role for E4F1 in the survival of myeloid leukemic cells and support the notion that targeting E4F1 activities might have therapeutic interest.

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