scholarly journals Programmed cell death proteins and chronic leukemia

2011 ◽  
Vol 63 (3) ◽  
pp. 527-535
Author(s):  
G. Brajuskovic ◽  
Milica Strnad ◽  
Snezana Cerovic ◽  
Stanka Romac
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Chronic Leukemia ◽  
Morphological Aspects ◽  
Pathological Conditions ◽  
Wide Range ◽  
Induction Of Apoptosis ◽  
Apoptotic Genes

Apoptosis or programmed cell death is a genetically regulated process of cellular suicide. Apoptosis has been implicated in a wide range of pathological conditions, and mutations in apoptotic genes play important roles in the process of malignant transformation. Chronic leukemia represents a neoplastic disorder caused primarily by defective programmed cell death, as opposed to increased cell proliferation. This paper presents the main results of our ten-year research on the apoptosis of leukemia cells. The research included the morphological aspects of the process, the effect of antineoplastic agents on the induction of apoptosis in leukemia cells and expression analysis of the proteins involved in programmed cell death. Special attention was paid to the expression and interaction of the Bcl-2 family of proteins in leukemia cells. The ultimate aim of the study of apoptosis of leukemic cells is the discovery of new biological agents that might be used in the treatment of chronic leukemia.

scholarly journals Apoptosis in malignant diseases

2005 ◽  
Vol 13 (1) ◽  
pp. 19-22 ◽  
Author(s):  
Goran Brajuskovic
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Tumor Regression ◽  
Current Knowledge ◽  
Biological Significance ◽  
Multistage Carcinogenesis ◽  
Pathological Conditions ◽  
Wide Range ◽  
Homeostatic Function ◽  
Apoptotic Genes

Apoptosis is a special type of cell death essentially different from necrosis in nature and biological significance. It is an active process of genetically regulated cell auto destruction and in most cases has a homeostatic function. Apoptotic cells may be characterized by specific morphological and biochemical changes. A great number of genes are known today, whose protein products take part in regulation of the apoptotic process. Apoptosis or programmed cell death has been implicated in a wide range of pathological conditions. Studies of the correlation of programmed cell death with proliferation and the multistage carcinogenesis process are in the focus of modern research. Mutations and deletions of apoptotic genes play important roles in carcinogenesis, tumor growth, and tumor regression. This article reviews the current knowledge on mutations of apoptosis genes involved in pathogenesis of human cancers. Finally, we have recently summarized achievements in cancer therapy with a focus on the apoptotic genes.

Aldehyde biphenyl chalcones induce immunogenic apoptotic-like cell death and are promising new safe compounds against a wide range of hematologic cancers

2020 ◽  
Vol 12 (8) ◽  
pp. 673-688
Author(s):  
Mariana F Maioral ◽  
Natália M Stefanes ◽  
Patrícia D Neuenfeldt ◽  
Louise D Chiaradia-Delatorre ◽  
Ricardo J Nunes ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Endoplasmic Reticulum Stress ◽  
Hematological Malignancies ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Promyelocytic Leukemia Protein ◽  
Wide Range ◽  
Antileukemic Effect

Aim: Investigate the apoptotic mechanisms of two new aldehyde biphenyl chalcones on leukemia cells. Materials & methods: From a series of 71 new chalcones, we selected the two most cytotoxic. Results: JA3 and JA7 were cytotoxic not only against hematological malignancies but also against solid tumor and cancer stem cells, yet with no toxicity to normal cells. Moreover, they induced immunogenic apoptotic-like cell death independently of promyelocytic leukemia protein, with extensive mitochondrial damages downstream of endoplasmic reticulum stress. Preventing endoplasmic reticulum stress and the upregulation of proapoptotic machinery inhibited JA3- and JA7-induced cell death. Likewise, blocking receptor Fas protected cells from killing. They increased the antileukemic effect of cytarabine and vincristine and killed leukemic cells collected from patients with different acute leukemia subtypes. Conclusion: JA3 and JA7 represent new promising prototypes for the development of new chemotherapeutics.

A novel mechanism for imatinib mesylate–induced cell death of BCR-ABL–positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2299-2307 ◽  
Author(s):  
Masayuki Okada ◽  
Souichi Adachi ◽  
Tsuyoshi Imai ◽  
Ken-ichiro Watanabe ◽  
Shin-ya Toyokuni ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Serine Protease ◽  
Imatinib Mesylate ◽  
Protease Activity ◽  
Kinase Inhibitor ◽  
Leukemic Cells ◽  
Endonuclease G ◽  
Serine Protease Activity ◽  
Human 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.

scholarly journals Lactadherin detects early phosphatidylserine exposure on immortalized leukemia cells undergoing programmed cell death

2006 ◽  
Vol 69A (12) ◽  
pp. 1193-1201 ◽  
Author(s):  
Jialan Shi ◽  
Yinan Shi ◽  
Lasse N. Waehrens ◽  
Jan T. Rasmussen ◽  
Christian W. Heegaard ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Leukemia Cells ◽  
Phosphatidylserine Exposure

Binary cell death decision regulated by unequal partitioning of Numb at mitosis

Development ◽  
2002 ◽  
Vol 129 (20) ◽  
pp. 4677-4684 ◽  
Author(s):  
Virginie Orgogozo ◽  
François Schweisguth ◽  
Yohanns Bellaïche
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Daughter Cell ◽  
Asymmetric Cell Divisions ◽  
Daughter Cells ◽  
Cell Divisions ◽  
Specific Manner ◽  
Asymmetric Divisions ◽  
Apoptotic Genes ◽  
Necessary And Sufficient

An important issue in Metazoan development is to understand the mechanisms that lead to stereotyped patterns of programmed cell death. In particular, cells programmed to die may arise from asymmetric cell divisions. The mechanisms underlying such binary cell death decisions are unknown. We describe here a Drosophila sensory organ lineage that generates a single multidentritic neuron in the embryo. This lineage involves two asymmetric divisions. Following each division, one of the two daughter cells expresses the pro-apoptotic genes reaper and grim and subsequently dies. The protein Numb appears to be specifically inherited by the daughter cell that does not die. Numb is necessary and sufficient to prevent apoptosis in this lineage. Conversely, activated Notch is sufficient to trigger death in this lineage. These results show that binary cell death decision can be regulated by the unequal segregation of Numb at mitosis. Our study also indicates that regulation of programmed cell death modulates the final pattern of sensory organs in a segment-specific manner.

scholarly journals Engagement of SIRPα Inhibits Growth and Induces Programmed Cell Death in Acute Myeloid Leukemia Cells

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e52143 ◽  
Author(s):  
Mahban Irandoust ◽  
Julian Alvarez Zarate ◽  
Isabelle Hubeek ◽  
Ellen M. van Beek ◽  
Karin Schornagel ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Programmed Cell Death ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

scholarly journals Anti-CHMP5 single chain variable fragment antibody retrovirus infection induces programmed cell death of AML leukemic cells in vitro

2012 ◽  
Vol 33 (6) ◽  
pp. 809-816 ◽  
Author(s):  
Hai-rong Wang ◽  
Zhen-yu Xiao ◽  
Miao Chen ◽  
Fei-long Wang ◽  
Jia Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Leukemic Cells ◽  
Single Chain Variable Fragment ◽  
Single Chain ◽  
Retrovirus Infection

Mitochondrial quality control in aging and lifespan control of the fungal aging model Podospora anserina

2011 ◽  
Vol 39 (5) ◽  
pp. 1488-1492 ◽  
Author(s):  
Heinz D. Osiewacz
Keyword(s):  
Quality Control ◽  
Cell Death ◽  
Life Cycle ◽  
Programmed Cell Death ◽  
Podospora Anserina ◽  
Molecular Pathways ◽  
Mitochondrial Quality Control ◽  
Wide Range ◽  
Fundamental Process ◽  
Hierarchical Manner

Aging of biological systems is a fundamental process controlled by a complex network of molecular pathways. In the filamentous fungus Podospora anserina, a model in which organismal aging can conveniently be analysed, mitochondria play a central role. A wide range of relevant pathways were identified that contribute to the maintenance of a population of functional mitochondria. These pathways act in a hierarchical manner, but all the pathways are limited in capacity. At the end of the life cycle, when the various surveillance pathways are overwhelmed and damage has passed certain thresholds, programmed cell death brings the life of individual P. anserina to an end.

scholarly journals Rapid induction of apoptosis by deregulated uptake of polyamine analogues

1997 ◽  
Vol 328 (1) ◽  
pp. 307-316 ◽  
Author(s):  
Rei-Huang HU ◽  
E. Anthony PEGG
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Oxidation Products ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Polyamine Biosynthesis ◽  
Polyamine Analogues ◽  
Induction Of Apoptosis

Treatment of Chinese hamster ovary cells with α-difluoromethylornithine for 3 days, followed by exposure to cycloheximide, led to an unregulated, rapid and massive accumulation of polyamine analogues. This accumulation led to cell death by apoptosis within a few hours. Clear evidence of DNA fragmentation was seen in response to both N-terminally ethylated polyamines and to polyamines containing methyl groups on the terminal carbon atoms. Programmed cell death was induced within 2-4 h of exposure to 1 μM or higher concentrations of N1,N11-bis(ethyl)norspermine. The presence of cycloheximide increased the uptake of the polyamine analogues and therefore led to cell death at lower analogue concentrations, but it was not essential for the induction of apoptosis, since similar effects were seen when the protein synthesis inhibitor was omitted and the concentration of N1,N11-bis(ethyl)norspermine was increased to 5 μM or more The induction of apoptosis was blocked both by the addition of the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, or by the addition of the polyamine oxidase inhibitor N1-methyl-N2-(2,3-butadienyl)butane-1,4-diamine (MDL 72,527). These experiments provide evidence to support the concepts that: (1) polyamines or their oxidation products may be initiators of programmed cell death; (2) regulation of polyamine biosynthesis and uptake prevents the accumulation of toxic levels of polyamines; and (3) the anti-neoplastic effects of bis(ethyl) polyamine analogues may be due to the induction of apoptosis in sensitive tumour cells.

scholarly journals Expression of PD-L1 in Leukemic Progenitor Cells Defines NPM1 Mutated AML As a Potential Subgroup for PD1/PD-L1 Directed Immunotherapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2734-2734
Author(s):  
Jochen Greiner ◽  
Vanessa Schneider ◽  
Hubert Schrezenmeier ◽  
Markus Wiesneth ◽  
Lars Bullinger ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Responses ◽  
Progenitor Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Significant Inhibition ◽  
Leukemic Cells ◽  
Advisory Committees ◽  
Oncology Research

Abstract Clinical and preclinical data suggest that acute myeloid leukemia (AML) with mutated nucleophosmin 1(NPM1mut) may constitute an immunogenic leukemia subtype. NPM1mut AML generally correlates with a better prognosis, however the underlying mechanisms still need to be clarified. Checkpoint inhibition targeting Programmed cell death protein 1 (PD-1)/Programmed cell death 1 ligand 1 (PD-L1) has been proven to be an effective novel immunotherapeutic approach in cancer treatment including the treatment of hematological malignancies. Expression of CD34/CD38/CD274 was evaluated in 20 NPM1mut versus 20 wild-type (NPM1wt) AML patient samples via flow cytometry analyses to assess PD-L1 (CD274) expression in leukemic cells, including leukemic progenitor and stem cells (LSC). We also investigated the influence of the anti-PD-1 antibody Nivolumab® on the antigen-specific immune responses in ELISpot assays. Additionally, we assessed the effect of Nivolumab in colony forming unit (CFU) immunoassays. Many AML cases showed relevant expression of PD-L1. Bulk cells of NPM1mut AML showed a significantly higher PD-L1 expression in comparison to NPM1wtAML patients (median of 1.5%, range 0.0-8.5%, versus 0.3%, range 0.1-1.1%). Importantly, PD-L1 expression was detected at a higher level in leukemic progenitor cells (CD34+CD38-) of NPM1mut than of NPM1wtAML (median of 3.3%, range 0.0-17.2%, versus 0.3%, range 0.0-3.0%). In general, the LSC fraction showed a higher PD-L1 expression than the non-LSC fraction. CFU immunoassays showed a significant inhibition of CFU when adding T cells stimulated against various LAA. In all patient samples, effectors activated against at least one LAA were successful to decrease the colony number significantly. Immune effects increased adding Nivolumab to the CTL for several days before starting CFU immunoassays. In summary, we detected higher PD-L1 expression in NPM1mut patients, especially in the leukemic progenitor compartment. This observation further supports the hypothesis that NPM1-directed immune responses might play an important role in tumor cell rejection, which tumor cells try to escape via expression of PD-L1. Immunogenicity of neoantigens derived from NPM1mut with higher PD-L1 expression constitute promising target structures for individualized immunotherapeutic approaches. Disclosures Schrezenmeier: Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Bullinger:Pfizer: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer Oncology: Research Funding. Döhner:Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria.

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