scholarly journals Cellular Iron Depletion and the Mechanisms Involved in the Iron-dependent Regulation of the Growth Arrest and DNA Damage Family of Genes

2011 ◽  
Vol 286 (41) ◽  
pp. 35396-35406 ◽  
Author(s):  
Federica Saletta ◽  
Yohan Suryo Rahmanto ◽  
Aritee R. Siafakas ◽  
Des R. Richardson
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Family Members ◽  
Growth Arrest ◽  
Regulatory Elements ◽  
Mrna Levels ◽  
Iron Depletion ◽  
Cellular Iron ◽  
Cycle Arrest

Iron plays a crucial part in proliferation while iron deficiency results in G1/S arrest, DNA damage, and apoptosis. However, the precise role of iron in cell cycle control remains unclear. We showed that iron depletion using the iron chelators, desferrioxamine (DFO), or 2-hydroxy-1-napthylaldehyde isonicotinoyl hydrazone (311), increased the mRNA levels of the growth arrest and DNA damage 45α gene, GADD45α (Darnell, G. and Richardson, D. R. (1999) Blood 94, 781–792). In this study, we examined the effect of iron depletion on up-regulating GADD family members involved in growth control, including cell cycle arrest, apoptosis, and DNA repair, making them therapeutic targets for tumor suppression. We showed the GADD family members were up-regulated by cellular iron depletion. Further, up-regulation of GADD45α after iron deprivation was independent of hypoxia-inducible factor-1α (HIF-1α), octamer-1 (Oct-1), p53 and early growth response 1 (Egr1). We then analyzed the regulatory elements responsible for iron depletion-mediated regulation of GADD45α and identified the specific transcription factor/s involved. This region was within −117 bp and −81 bp relative to the start codon where the consensus sequences of three transcription factors are located: the CCAAT-binding factor/nuclear factor-Y (NF-Y), the stabilizing molecule v-MYB and the enhancer, CCAAT enhancer-binding protein (CEBPα). Mutation analysis, shRNA studies, Western blotting, and electrophoretic mobility shift assays led to the identification of NF-Y in the transcriptional up-regulation of GADD45α after iron depletion. Furthermore, like GADD45α, NF-YA was up-regulated after iron chelation and down-regulated by iron supplementation. These results are important for understanding the mechanisms of iron depletion-mediated cell cycle arrest, DNA damage repair, and apoptosis.

DNA damage–induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway

Blood ◽  
2001 ◽  
Vol 98 (3) ◽  
pp. 834-841 ◽  
Author(s):  
Matthew K. Henry ◽  
Jeffrey T. Lynch ◽  
Alex K. Eapen ◽  
Frederick W. Quelle
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Signaling Pathway ◽  
Growth Arrest ◽  
Hematopoietic Cells ◽  
Akt Signaling ◽  
Dominant Negative ◽  
Akt Signaling Pathway ◽  
Cycle Arrest

Abstract Exposure of hematopoietic cells to DNA-damaging agents induces cell-cycle arrest at G1 and G2/M checkpoints. Previously, it was shown that DNA damage–induced growth arrest of hematopoietic cells can be overridden by treatment with cytokine growth factors, such as erythropoietin (EPO) or interleukin-3 (IL-3). Here, the cytokine-activated signaling pathways required to override G1 and G2/M checkpoints induced by γ-irradiation (γ-IR) are characterized. Using factor-dependent myeloid cells stably expressing EPO receptor (EPO-R) mutants, it is shown that removal of a minimal domain required for PI-3K signaling abrogated the ability of EPO to override γ-IR–induced cell-cycle arrest. Similarly, the ability of cytokines to override γ-IR–induced arrest was abolished by an inhibitor of PI-3K (LY294002) or by overexpression of dominant-negative Akt. Moreover, the ability of EPO to override these checkpoints in cells expressing defective EPO-R mutants could be restored by overexpression of a constitutively active Akt. Thus, activation of a PI-3K/Akt signaling pathway is required for cytokine-dependent suppression of DNA-damage induced checkpoints. Together, these findings suggest a novel role for PI-3K/Akt pathways in the modulation of growth arrest responses to DNA damage in hematopoietic cells.

Impaired S Phase Arrest in AML Cells with a FLT3-ITD Treated with Clofarabine Allows Prolonged Drug exposure to Reverse the Chemoresistant Phenotype.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1000-1000
Author(s):  
Claire Seedhouse ◽  
Martin Grundy ◽  
Shili Shang ◽  
John Ronan ◽  
Heather Pimblett ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Cycle Arrest ◽  
Short Pulse ◽  
S Phase ◽  
Mrna Levels ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
S Phase Arrest

Abstract Abstract 1000 Poster Board I-22 We have previously reported that AML cells with a FLT3-ITD have enhanced DNA repair mechanisms following exposure to DNA-damaging drugs which may be a mechanism of chemoresistance. Clofarabine is a novel nucleoside analogue, active in S-phase, with efficacy in AML and is incorporated into DNA as clofarabine triphosphate. Here we show that in FLT3-ITD cells enhanced repair, and therefore resistance to clofarabine-induced DNA damage and toxicity, can be reversed by prolonged drug incubation. When treated with clofarabine, FLT3-ITD-harbouring MOLM13 and MV4.11 cells undergo similar levels of DNA damage (γH2A.X foci) to FLT3 wildtype (WT) cells (HL60 and KG1). After a short pulse of drug the FLT3-ITD cells have a superior repair capability than WT cells; following a 2 hour washout period γH2A.X positivity found immediately after treatment had almost completely disappeared in the FLT3-ITD cells (<10% γH2A.X remaining), whereas in the FLT3-WT cells significant damage (γH2A.X) remained (>40%). Furthermore, after a 1 hour pulse of clofarabine, whereas the FLT3-WT cells under go rapid S phase arrest the S-phase checkpoint fails in the FLT3-ITD cells: reduction in the proportion of cells synthesising DNA is >80% in FLT3-WT cells and <10% in FLT3-ITD cells. Cell cycle arrest in response to DNA damage in S phase is affected via loss of the transcriptional regulator cdc25A. This loss of expression of cdc25A fails to take place in clofarabine-treated FLT3 mutant cells compared to WT cells. In addition, cdc25A mRNA levels are maintained by the FLT3-ITD as demonstrated by siRNA to FLT3 which reduced cdc25A mRNA levels in MV4.11 cells by 87.5%. Primary FLT3 mutant samples from AML patients(n=3) also display impaired cell cycle arrest upon treatment with clofarabine and show enhanced sensitivity on prolonged treatment (24 hours) compared to wildtype samples (n=2). We conclude that there is a reversal of phenotype in mutant FLT3 cells dependant on the length of exposure to clofarabine. Efficient DNA repair renders the cells resistant to a short pulse of the drug, but a failure of cell cycle checkpoint(s) in S phase, mediated by cdc25A, renders the cells sensitive to prolonged exposure. These results may have implications for the scheduling of clofarabine in clinical studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Design, Synthesis and Pharmacological Evaluation of Three Novel Dehydroabietyl Piperazine Dithiocarbamate Ruthenium (II) Polypyridyl Complexes as Potential Antitumor Agents: DNA Damage, Cell Cycle Arrest and Apoptosis Induction

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1453
Author(s):  
Haoran Wang ◽  
Jianhua Wei ◽  
Hong Jiang ◽  
Ye Zhang ◽  
Caina Jiang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Antitumor Agents ◽  
Mechanistic Study ◽  
Ros Generation ◽  
Polypyridyl Complexes ◽  
Expression Levels ◽  
Cycle Arrest ◽  
Study Results

The use of cisplatin is severely limited by its toxic side-effects, which has spurred chemists to employ different strategies in the development of new metal-based anticancer agents. Here, three novel dehydroabietyl piperazine dithiocarbamate ruthenium (II) polypyridyl complexes (6a–6c) were synthesized as antitumor agents. Compounds 6a and 6c exhibited better in vitro antiproliferative activity against seven tumor cell lines than cisplatin, they displayed no evident resistance in the cisplatin-resistant cell line A549/DPP. Importantly, 6a effectively inhibited tumor growth in the T-24 xenograft mouse model in comparison with cisplatin. Gel electrophoresis assay indicated that DNA was the potential targets of 6a and 6c, and the upregulation of p-H2AX confirmed this result. Cell cycle arrest studies demonstrated that 6a and 6c arrested the cell cycle at G1 phase, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of cyclin E. In addition, 6a and 6c caused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-9, cytochrome c, intracellular Ca2+ release, reactive oxygen species (ROS) generation and the downregulation of Bcl-2. These mechanistic study results suggested that 6a and 6c exerted their antitumor activity by inducing DNA damage, and consequently causing G1 stage arrest and the induction of apoptosis.

scholarly journals ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53.

2002 ◽  
Vol 277 (23) ◽  
pp. 21110 ◽  
Author(s):  
Damu Tang ◽  
Dongcheng Wu ◽  
Atsushi Hirao ◽  
Jill M. Lahti ◽  
Lieqi Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Erk Activation ◽  
Cycle Arrest

scholarly journals P28-10 Cisplatin induces DNA damage associated with cell cycle arrest and apoptosis in PC9 cells

2021 ◽  
Vol 32 ◽  
pp. S346
Author(s):  
Md Mohiuddin ◽  
Hideharu Kimura ◽  
Takashi Sone ◽  
Hiroki Matsuoka ◽  
Keigo Saeki ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cycle Arrest

scholarly journals Aqueous Extracts of the Edible Gracilaria tenuistipitata are Protective Against H2O2-Induced DNA Damage, Growth Inhibition, and Cell Cycle Arrest

Molecules ◽  
2012 ◽  
Vol 17 (6) ◽  
pp. 7241-7254 ◽  
Author(s):  
Jing-Iong Yang ◽  
Chi-Chen Yeh ◽  
Jin-Ching Lee ◽  
Szu-Cheng Yi ◽  
Hurng-Wern Huang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Growth Inhibition ◽  
Cell Cycle Arrest ◽  
Aqueous Extracts ◽  
Damage Growth ◽  
Gracilaria Tenuistipitata ◽  
Cycle Arrest

Mollugin induced oxidative DNA damage via up-regulating ROS that caused cell cycle arrest in hepatoma cells

2022 ◽  
pp. 109805
Author(s):  
Xin-ge Ke ◽  
Yi-yi Xiong ◽  
Bing Yu ◽  
Chong Yuan ◽  
Peng-yu Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Oxidative Dna Damage ◽  
Hepatoma Cells ◽  
Cycle Arrest

Octadecyloxyethyl Adefovir Exhibits Potent in vitro and in vivo Cytotoxic Activity and Has Synergistic Effects with Ara-C in Acute Myeloid Leukemia

Chemotherapy ◽  
2018 ◽  
Vol 63 (4) ◽  
pp. 225-237 ◽  
Author(s):  
Haytham Khoury ◽  
Ruijuan He ◽  
Aaron Schimmer ◽  
James R. Beadle ◽  
Karl Y. Hostetler ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Cell Cycle Arrest ◽  
Clinical Benefit ◽  
Myeloid Leukemia ◽  
Mouse Bone Marrow ◽  
Medical Needs ◽  
Cycle Arrest ◽  
Acute Myeloid

Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50–70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this screen, we discovered adefovir dipi­voxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcome the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir were highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of > 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was through cell cycle arrest and DNA damage. Indeed, ODE-adefovir treatment induced cell cycle arrest in the S phase and increased levels of pH2Ax, indicating the induction of DNA damage. Furthermore, there was an increase in phospho-p53, transactivation of proapoptotic genes and activation of the intrinsic apoptotic pathway. Subsequent investigation unveiled strong synergism between ODE-adefovir and ara-C, making their coadministration of potential clinical benefit. Expression of MRP4, a nucleoside transporter, appeared to influence the response of AML cells to ODE-adefovir, as its inhibition potentiated ODE-adefovir killing. Taken together, our findings indicate that clinical development of ODE-adefovir or related compounds for the treatment of AML is warranted.

scholarly journals RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Toshinori Ozaki ◽  
Akira Nakagawara ◽  
Hiroki Nagase
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Apoptotic Cell ◽  
Genetic Alterations ◽  
Apoptotic Cell Death ◽  
Cycle Arrest ◽  
Damage Response

A proper DNA damage response (DDR), which monitors and maintains the genomic integrity, has been considered to be a critical barrier against genetic alterations to prevent tumor initiation and progression. The representative tumor suppressor p53 plays an important role in the regulation of DNA damage response. When cells receive DNA damage, p53 is quickly activated and induces cell cycle arrest and/or apoptotic cell death through transactivating its target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death such asp21WAF1,BAX, andPUMA. Accumulating evidence strongly suggests that DNA damage-mediated activation as well as induction of p53 is regulated by posttranslational modifications and also by protein-protein interaction. Loss of p53 activity confers growth advantage and ensures survival in cancer cells by inhibiting apoptotic response required for tumor suppression. RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor and is closely involved in a variety of cellular processes including development, differentiation, and/or tumorigenesis. In this review, we describe a background of p53 and a functional collaboration between p53 and RUNX family in response to DNA damage.

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