The Role of Apoptosis in Cancer Development and Treatment: Focusing on the Development and Treatment of Hematologic Malignancies

Živný, J; Klener, Pavel; Pytlik, Robert; Anděra, Ladislav

doi:10.2174/138161210789941883

Cited by 39 publications

(26 citation statements)

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“…In this process, the plasma membrane remains whole, but undergoes structural alterations, such as the distribution of phosphatidylserine on the outer layer of the membrane, which is a signal for phagocyte recognition 15 . In this manner, the dead cell is quickly removed without leakage of cytoplasmic content, thus avoiding an intense inflammatory response 6 .…”

Section: Apoptosismentioning

confidence: 99%

“…In this process, senescent or damaged cells are eliminated after activation of a cell death program involving participation of pro-apoptotic molecules (Fas, Bax, caspases 2,3,6,7, 8 and 9). Molecule activation causes typical morphological changes, such as cell shrinkage, loss of adhesion to the extracellular matrix and neighboring cells, chromatin condensation, DNA fragmentation and formation of apoptotic bodies.…”

Section: Introductionmentioning

confidence: 99%

“…When unregulated, apoptosis could contribute to the appearance of various neoplastic, autoimmune and neurodegenerative diseases 2,5,6 .…”

Section: Introductionmentioning

confidence: 99%

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Melatonina: modulador de morte celular

Ferreira

Maganhin

Simões

et al. 2010

Rev. Assoc. Med. Bras.

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Apoptosis or planned cell death is a biological phenomenon that is essential for the development and maintenance of a cell population. In this process, senescent or damaged cells are eliminated after activation of a cell death program involving participation of pro-apoptotic molecules (Fas, Bax, caspases 2,3,6,7, 8 and 9). Molecule activation causes typical morphological changes, such as cell shrinkage, loss of adhesion to the extracellular matrix and neighboring cells, chromatin condensation, DNA fragmentation and formation of apoptotic bodies. Anti-apoptotic molecules (Bcl-2, FLIP) block the emergence and evolution of these cell changes and prevent cell death. The balance between pro-and anti-apoptotic molecules ensures tissue homeostasis. When apoptosis is out of control, it contributes to the emergence of several neoplastic, autoimmune and neurodegenerative diseases. Several inducing and inhibiting agents of apoptosis are recognized as potential weapons in the fight against disorders related to cell proliferation and death among, among which stand hormones out. Melatonin has been reported as an important anti-apoptotic agent in various tissues by reducing cell calcium uptake, mitigating the production of oxygen reactive species and decreasing pro-apoptotic proteins, such as Bax. The knowledge of new agents capable of acting on the course of apoptosis is important and valuable for developing further therapies against various diseases. Thus, the objective of this review was to clarify the main aspects of cell death by apoptosis and the role of melatonin in this process

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Section: Apoptosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Melatonina: modulador de morte celular

Ferreira

Maganhin

Simões

et al. 2010

Rev. Assoc. Med. Bras.

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“…Consequently, proteins of the BCL-2 family appear to be suitable targets for therapies in cancer. 13 To this end, it is crucial to identify the molecules that regulate the apoptotic machinery as well as their downstream effectors.Here, we explored how Spi-1 induces resistance to apoptosis in the preleukaemic erythroid progenitors of the Spi-1 transgenic mice. We found that Spi-1 inhibits mitochondrial apoptosis both in vitro and in vivo through transcriptional repression of Bim.…”

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confidence: 99%

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confidence: 99%

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

et al. 2013

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Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression. Cell Death and Differentiation (2013) 20, 1268-1278; doi:10.1038/cdd.2013.88; published online 12 July 2013Acute myeloid leukaemia (AML) develops through a multistep process driven by the progressive accumulation of mutations, leading to deregulation of cell proliferation and differentiation. Most frequently, abnormalities in cell differentiation are the result of loss-of-function mutations in lineage-specific transcription factors, whereas alterations in cell proliferation are associated with gain-of-function mutations in signalling pathways. 1 Mutations that target components of the spliceosomal machinery 2 and epigenetic regulators 3 have been identified as well, although their functional consequences in leukaemogenesis are not clear. To date, AML treatments are largely determined by the nature of the identified mutated proteins and a major challenge is to design molecules that can target each molecular alteration contributing to transformation. For that, understanding the molecular mechanisms controlled by an oncoprotein is one essential step. We have previously described a mouse model of erythroleukaemia (Spi-1 transgenic mice) that recapitulates the multistep development of human AML. 4 Spi-1 is a master transcription factor of haematopoiesis that is also involved in pre-mRNA splicing regulation. 5 During the preleukaemic stage of the disease, the differentiation blockage of the erythroid progenitors is the first oncogenic mark assoc...

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Synthesis and Cytotoxicity Studies of Novel 2‐Hydrazonylpyrido[2,3‐b]pyrazin‐3(4H)‐ones

Zhang

Liu

Wang

et al. 2011

Archiv der Pharmazie

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In an attempt to develop potent antitumor agents, a series of novel 2-hydrazonylpyrido[2,3-b]pyrazin-3(4H)-one derivatives were designed and synthesized. All the prepared compounds were screened for their cytotoxic activities against A549, MDA-MB-231 and HT-29 cell lines in vitro. Pharmacological data indicated that five of the target compounds showed cytotoxicity against A549 cell line below a concentration of 1 µM. Compound 15g was the most potent one with IC(50) values of 0.19, 2.11 and 2.15 µM against A549, MDA-MB-231 and HT29 cell lines, respectively.

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The Role of Apoptosis in Cancer Development and Treatment: Focusing on the Development and Treatment of Hematologic Malignancies

Cited by 39 publications

References 0 publications

Melatonina: modulador de morte celular

Melatonina: modulador de morte celular

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

Synthesis and Cytotoxicity Studies of Novel 2‐Hydrazonylpyrido[2,3‐b]pyrazin‐3(4H)‐ones

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