Epigenetic modulation of gene expression of human leukemia cell lines – induction of cell death and senescence

Elknerová, Klára; Myslivcová, Denisa; Lacinová, Z; Marinov, Iuri; Uherková, Lenka; Stöckbauer, P

doi:10.4149/neo_2011_01_35

Cited by 24 publications

(17 citation statements)

References 29 publications

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“…The significant decrease in mitotic indices revealed with the 5.0 mM VPA treatment for 48 h indicates that relatively long periods of treatment and/or high doses of this drug are required for an effect on HeLa cell proliferation, which confirms previous data for this cell line [16] and is also consistent with a report for leukemic cells [33]. Conversely, even under this antiproliferative condition, no effect was verified on the frequency of cell death, as determined by morphology in Feulgen-stained preparations, which was used for the calculation of cell death ratios in VPA-treated HeLa cells.…”

Section: Discussionsupporting

confidence: 91%

“…HDACis have also been implicated in the cell cycle arrest and apoptosis intrinsic and extrinsic pathways, inducing the expression of genes encoding cell death receptors and their cognate ligands or mediating the repression of genes that encode inhibitors of these pathways [18], [25]–[33]. In addition to eliciting apoptotic pathways, HDACis have been reported to be involved with the induction of autophagic cell death, mitotic cell death and senescence in various transformed cell lines [27], [33].…”

Section: Introductionmentioning

confidence: 99%

“…In addition to eliciting apoptotic pathways, HDACis have been reported to be involved with the induction of autophagic cell death, mitotic cell death and senescence in various transformed cell lines [27], [33]. Acetylation of non-histone proteins by HDACis may account for their reported antitumor responses or synergistic effects when HDACis are combined with pro-apoptotic agents [26], [27], [31].…”

Section: Introductionmentioning

confidence: 99%

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Chromatin Remodeling, Cell Proliferation and Cell Death in Valproic Acid-Treated HeLa Cells

2011

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BackgroundValproic acid (VPA) is a potent anticonvulsant that inhibits histone deacetylases. Because of this inhibitory action, we investigated whether VPA would affect chromatin supraorganization, mitotic indices and the frequency of chromosome abnormalities and cell death in HeLa cells.Methodology/Principal FindingsImage analysis was performed by scanning microspectrophotometry for cells cultivated for 24 h, treated with 0.05, 0.5 or 1.0 mM VPA for 1–24 h, and subjected to the Feulgen reaction. TSA-treated cells were used as a predictable positive control. DNA fragmentation was investigated with the TUNEL assay. Chromatin decondensation was demonstrated under TSA and all VPA treatments, but no changes in chromosome abnormalities, mitotic indices or morphologically identified cell death were found with the VPA treatment conditions mentioned above, although decreased mitotic indices were detected under higher VPA concentration and longer exposure time. The frequency of DNA fragmentation identified with the TUNEL assay in HeLa cells increased after a 24-h VPA treatment, although this fragmentation occurred much earlier after treatment with TSA.Conclusions/SignificanceThe inhibition of histone deacetylases by VPA induces chromatin remodeling in HeLa cells, which suggests an association to altered gene expression. Under VPA doses close to the therapeutic antiepileptic plasma range no changes in cell proliferation or chromosome abnormalities are elicited. The DNA fragmentation results indicate that a longer exposure to VPA or a higher VPA concentration is required for the induction of cell death.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chromatin Remodeling, Cell Proliferation and Cell Death in Valproic Acid-Treated HeLa Cells

2011

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“…Playing a cytoprotective role in cancer cells, autophagy acts as an antagonist to such a powerful tumor-suppressor mechanism as cellular senescence, wherein cells permanently arrest their proliferation even in the presence of strong mitogenic signals [ 23 - 27 ]. Cancer cells expressing wild-type p53 can be induced to senescence by a variety of stimuli, including stresses, irradiation, starvation and histone deacetylase inhibitors (HDACi) [ 28 - 30 ]. Senescent cells do not proliferate but maintain viability and continue to synthesize proteins and to secrete the inflammatory cytokines and growth factors (SASP phenotype) [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted elimination of senescent Ras-transformed cells by suppression of MEK/ERK pathway

Кочеткова

Blinova

Bystrova

et al. 2017

Aging

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The Ras-Raf-MEK-ERK pathway plays a central role in tumorigenesis and is a target for anticancer therapy. The successful strategy based on the activation of cell death in Ras-expressing cells is associated with the suppression of kinases involved in Ras pathway. However, activation of cytoprotective autophagy overcomes antiproliferative effect of the inhibitors and develops drug resistance. We studied whether cellular senescence induced by HDAC inhibitor sodium butyrate in E1a+cHa-Ras-transformed rat embryo fibroblasts (ERas) and A549 human Ki-Ras mutated lung adenocarcinoma cells would enhance the tumor suppressor effect of MEK/ERK inhibition. Treatment of control ERas cells with PD0325901 for 24 hresults in mitochondria damage and apoptotic death of a part of cellular population. However, the activation of AMPK-dependent autophagy overcomes pro-apoptotic effects of MEK/ERK inhibitor and results in restoration of the mitochondria and rescue of viability. Senescent ERas cells do not develop cytoprotective autophagy upon inhibition of MEK/ERK pathway due to spatial dissociation of lysosomes and autophagosomes in the senescent cells. Senescent cells are unable to form the autophagolysosomes and to remove the damaged mitochondria resulting in apoptotic death. Our data show that suppression of MEK/ERK pathway in senescent cells provides a new strategy for elimination of Ras-expressing cells.

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“…VPA perpetuates its effects by up-regulating cyclin-dependent kinase inhibitor 1A, BCLA1, and p53, whereas proto-oncogene (c-Myc, BCL2, BCL-XL, Ataxia-Telangiectasia Mutated, protein kinase B) were downregulated, thereby augmenting mTOR inhibitor to induce autophagic cell death in several kinds of lymphomas including Burkitt leukemia/lymphoma, cutaneous T cell lymphoma and CLL ( 153 , 154 ). Furthermore, VPA alone or in combination with other drugs, such as fludarabine, flavopiridol, cladribine, lenalidomide, and bortezomib is highly effective in inducing cell death in CLL cells and could be considered for therapeutic intervention ( 155 , 156 ).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Molecular Interactions Between Innate and Adaptive Immune Cells in Chronic Lymphocytic Leukemia and Their Therapeutic Implications

2018

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Innate immunity constitutes the first line of host defense against various anomalies in humans, and it also guides the adaptive immune response. The function of innate immune components and adaptive immune components are interlinked in hematological malignancies including chronic lymphocytic leukemia (CLL), and molecular interactions between innate and adaptive immune components are crucial for the development, progression and the therapeutic outcome of CLL. In this leukemia, genetic mutations in B cells and B cell receptors (BCR) are key driving factors along with evasion of cytotoxic T lymphocytes and promotion of regulatory T cells. Similarly, the release of various cytokines from CLL cells triggers the protumor phenotype in macrophages that further edges the CLL cells. Moreover, under the influence of various cytokines, dendritic cells are unable to mature and trigger T cell mediated antitumor response. The phenotypes of these cells are ultimately controlled by respective signaling pathways, the most notables are BCR, Wnt, Notch, and NF-κB, and their activation affects the cytokine profile that controls the pathogenesis of CLL, and challenge its treatment. There are several novel substances for CLL under clinical development, including kinase inhibitors, antibodies, and immune-modulators that offer new hopes. DC-based vaccines and CAR T cell therapy are promising tools; however, further studies are required to precisely dissect the molecular interactions among various molecular entities. In this review, we systematically discuss the involvement, common targets and therapeutic interventions of various cells for the better understanding and therapy of CLL.

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Epigenetic modulation of gene expression of human leukemia cell lines – induction of cell death and senescence

Cited by 24 publications

References 29 publications

Chromatin Remodeling, Cell Proliferation and Cell Death in Valproic Acid-Treated HeLa Cells

Chromatin Remodeling, Cell Proliferation and Cell Death in Valproic Acid-Treated HeLa Cells

Targeted elimination of senescent Ras-transformed cells by suppression of MEK/ERK pathway

Molecular Interactions Between Innate and Adaptive Immune Cells in Chronic Lymphocytic Leukemia and Their Therapeutic Implications

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