scholarly journals Zalypsis has in vitro activity in acute myeloid blasts and leukemic progenitor cells through the induction of a DNA damage response

Haematologica ◽  
2011 ◽  
Vol 96 (5) ◽  
pp. 687-695 ◽  
Author(s):  
E. Colado ◽  
T. Paino ◽  
P. Maiso ◽  
E. M. Ocio ◽  
X. Chen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Progenitor Cells ◽  
Dna Damage Response ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Damage Response ◽  
Acute Myeloid

The Telomerase Inhibitor RHPS4 Induces Telomere Shortening, DNA-Damage and Cell Death in AML Cells and Chemosensitises Cells to Daunorubicin.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2760-2760
Author(s):  
Monica Pallis ◽  
Dotun Ojo ◽  
Jaineeta Richardson ◽  
John Ronan ◽  
Malcolm Stevens ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Telomere Length ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Cell Types ◽  
Telomere Shortening ◽  
Damage Response

Abstract Abstract 2760 Poster Board II-736 The quadruplex ligand RHPS4 is the lead compound in a drug discovery program at the University of Nottingham. It has been shown to bind to telomeres and inhibit telomerase, and subsequently induces growth arrest in progenitor cells from cancer cell lines whilst sparing normal haematopoietic progenitor cells. We explored its in vitro effects in AML cells, which are reported generally to have considerably shorter telomeres than normal CD34+ cells. AML cell lines were grown for 21 days in suspension culture. Primary samples were cultured for 14 days in semi-solid medium. Telomere length was measured by Southern blotting. γH2A.X was used to identify a DNA damage response, and cell viability was measured flow cytometrically with 7-amino actinomycin D. As reported in other tumour cell types, sensitivity to RHPS4 was found to be greatest in those AML cells with the shortest telomeres. In the OCI-AML3 cell line 0.3 μM RHPS4 inhibited cell growth by 50% in a 21 day clonogenic assay, accompanied by shortening of telomeres from 2.6 Kb to <1 Kb. Molm 13 cells (initial telomere length 3.2kB) also underwent telomere shortening in the presence of 0.3 μM RHPS4 (2.8Kb), whereas TF1a and U937 (both with initial telomere lengths approximately 6.5 kB) were insensitive at that concentration. After 6 days at 0.3 μM, RHPS4 was cytostatic, but at higher concentrations (1 μM) the drug was found to induce a substantial DNA damage response and loss of viability to OCI-AML3 cells. Moreover 0.3 μM RHPS4 enhanced the γH2A.X expression and cell death induced by the chemotherapy drug daunorubicin in these cells. Using 14 day clonogenic assays in primary AML samples (n=6), we found that the IC50 for RHPS4 alone was 0.7 μM. However, in the presence of 0.3 μM RHPS4, the median IC50 to daunorubicin was reduced from 19 nM to 5.5 nM. In conclusion we have determined that RHPS4 has telomere-shortening, cytostatic, cytotoxic and chemosensitising properties in AML cells. Disclosures: Stevens: Pharminox Ltd: director and shareholder of Pharminox Ltd which has a financial interest in RHPS4.

scholarly journals DNMT3A-NPM1 mutated acute myeloid leukaemia shows sensitivity to a PARP1 inhibitor combined with daunorubicin in an in vitro model

2018 ◽  
Author(s):  
Grigore Gafencu ◽  
Valentina Pileczki ◽  
Ancuta Jurj ◽  
Lorand Magdo ◽  
Cristina Selicean ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Dna Damage Response ◽  
Parp Inhibitors ◽  
Damage Response ◽  
Vitro Model ◽  
New Treatment ◽  
Acute Myeloid

SummaryAcute myeloid leukaemia is a neoplasia in need of new treatment approaches. PARP inhibitors are a class of targeted therapeutics for cancer that disrupts dysfunctional DNA damage response in various neoplasia. MLL-AF9 mutated leukaemias are sensitive to combinations of PARP inhibitors and cytotoxic drugs. Moreover, DNMT3A and NPM1 mutations are linked to dysfunctions in DNA damage response. Therefore, we investigated if DNMT3A-NPM1 mutated AML cell line is sensible to PARP inhibitors combined with anthracyclines. Our results show that DNMT3A-NPM1 mutated AML is as sensible to combinations of PARP inhibitors and anthracyclines as MLL-AF9 mutated leukaemias, in an in vitro setting.

Induction of DNA Damage Response and Repair Pathways in HSPCs Following Exposure to AML Exosomes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4324-4324 ◽  
Author(s):  
Jennifer Wherley ◽  
Ashley N. Kamimae-Lanning ◽  
Natalya A. Goloviznina ◽  
Jianya Huan ◽  
Peter Kurre
Keyword(s):  
Dna Damage ◽  
Cell Line ◽  
Progenitor Cells ◽  
Dna Damage Response ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Damage Response ◽  
Repair Pathways ◽  
Bystander Cells

Abstract Exosomes are extracellular vesicles that function in cell-cell communication by trafficking protein and RNA species to bystander cells. While exosomes are produced by all cell types, those released by cancer cells have come to the forefront of investigation for their potential to modulate the tumorigenic niche. We recently reported that exosomes released from acute myelogenous leukemia (AML) cells impact the phenotype and function of stromal and hematopoietic stem and progenitor cells (HSPC) found in the bone marrow (Huan et al. Cancer Res. 2013). As part of these studies, we observed a decrease in clonogenic potential of murine HSPCs exposed to exosomes isolated from the Molm-14 AML cell line in vitro and in xenograft transplantation studies. To determine if this observation was more widely applicable, we next exposed murine c-kit-selected HSPCs to exosomes isolated from both primary patient samples and the HL-60 AML cell line in vitro. Strikingly, exposure to primary AML patient and HL-60 exosomes produced a significant reduction in colony formation; on average, only 7.3% as many colonies formed in exposed conditions compared to controls. We also previously showed that exosomes traffic a complex mixture of protein and RNA to bystander cells. A recent report demonstrated increased DNA damage in mammary epithelial cells due to elevated reactive oxygen species (ROS) following exposure to exosomes derived from multiple breast cancer cell lines (Dutta et al. PLOS One 2014). A similar mechanism has been shown to restrict the replicative capacity of human HSPCs. Here, we hypothesized that exosome transfer might elicit a DNA damage response in murine HSPCs, contributing to the decreased ability of exposed cells to form colonies. When we performed 48 hours of in vitro HL-60 exosome exposure of c-kit enriched progenitor cells, we found a statistically significant upregulation of genes involved in DNA damage sensing as well as homologous recombination (HR) and non-homologous end joining (NHEJ) DNA repair pathways compared to unexposed controls. Immunofluorescence analysis on exosome-exposed cells also revealed an increase in the formation of γH2AX foci in cells exposed to HL-60 exosomes, indicating an increase in DNA damage burden. Next, we tested if increased ROS might account for DNA damage and the resulting progenitor frequency. Using a flow cytometric analysis of ROS (DCF-DA) revealed a clear upward shift in median fluorescence intensity of exosome-treated c-kit+ cells compared to untreated controls. To further confirm the involvement of ROS, we treated exosome-exposed cells with the antioxidant NAC. While this did not result in a substantial reduction in ROS levels as measured by flow cytometry, analysis of the transcriptional DNA damage response revealed a dose-response pharmacological rescue of HR and NHEJ pathway gene expression. Our work in aggregate suggests that AML exosomes have a direct suppressive effect on HSPCs that involves, at least in part, gains in ROS that promote DNA damage accumulation and genomic instability. We propose a model whereby the paracrine trafficking of exosomes plays an active role in the erosion of HSPC activity in the AML niche that leads to characteristic cytopenias even at low leukemic burden. Disclosures No relevant conflicts of interest to declare.

scholarly journals The DNA damage inducible lncRNA SCAT7 regulates genomic integrity and topoisomerase 1 turnover in lung adenocarcinoma

NAR Cancer ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Luisa Statello ◽  
Mohamad M Ali ◽  
Silke Reischl ◽  
Sagar Mahale ◽  
Subazini Thankaswamy Kosalai ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cancer Biology ◽  
Topoisomerase I ◽  
Cell Cycle Checkpoints ◽  
Topoisomerase 1 ◽  
Damage Response ◽  
Promote Cell Survival

Abstract Despite the rapid improvements in unveiling the importance of lncRNAs in all aspects of cancer biology, there is still a void in mechanistic understanding of their role in the DNA damage response. Here we explored the potential role of the oncogenic lncRNA SCAT7 (ELF3-AS1) in the maintenance of genome integrity. We show that SCAT7 is upregulated in response to DNA-damaging drugs like cisplatin and camptothecin, where SCAT7 expression is required to promote cell survival. SCAT7 silencing leads to decreased proliferation of cisplatin-resistant cells in vitro and in vivo through interfering with cell cycle checkpoints and DNA repair molecular pathways. SCAT7 regulates ATR signaling, promoting homologous recombination. Importantly, SCAT7 also takes part in proteasome-mediated topoisomerase I (TOP1) degradation, and its depletion causes an accumulation of TOP1–cc structures responsible for the high levels of intrinsic DNA damage. Thus, our data demonstrate that SCAT7 is an important constituent of the DNA damage response pathway and serves as a potential therapeutic target for hard-to-treat drug resistant cancers.

scholarly journals PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1/2

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Nan Huang ◽  
Chang Xu ◽  
Liang Deng ◽  
Xue Li ◽  
Zhixuan Bian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Histone Deacetylase ◽  
Dna Damage Response ◽  
De Novo ◽  
Dna Damage Repair ◽  
Histone Deacetylase 1 ◽  
Damage Repair ◽  
Damage Response

AbstractPhosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an essential enzyme involved in de novo purine biosynthesis, is connected with formation of various tumors. However, the specific biological roles and related mechanisms of PAICS in gastric cancer (GC) remain unclear. In the present study, we identified for the first time that PAICS was significantly upregulated in GC and high expression of PAICS was correlated with poor prognosis of patients with GC. In addition, knockdown of PAICS significantly induced cell apoptosis, and inhibited GC cell growth both in vitro and in vivo. Mechanistic studies first found that PAICS was engaged in DNA damage response, and knockdown of PAICS in GC cell lines induced DNA damage and impaired DNA damage repair efficiency. Further explorations revealed that PAICS interacted with histone deacetylase HDAC1 and HDAC2, and PAICS deficiency decreased the expression of DAD51 and inhibited its recruitment to DNA damage sites by impairing HDAC1/2 deacetylase activity, eventually preventing DNA damage repair. Consistently, PAICS deficiency enhanced the sensitivity of GC cells to DNA damage agent, cisplatin (CDDP), both in vitro and in vivo. Altogether, our findings demonstrate that PAICS plays an oncogenic role in GC, which act as a novel diagnosis and prognostic biomarker for patients with GC.

scholarly journals Dephosphorylation of the C-terminal Tyrosyl Residue of the DNA Damage-related Histone H2A.X Is Mediated by the Protein Phosphatase Eyes Absent

2009 ◽  
Vol 284 (24) ◽  
pp. 16066-16070 ◽  
Author(s):  
Navasona Krishnan ◽  
Dae Gwin Jeong ◽  
Suk-Kyeong Jung ◽  
Seong Eon Ryu ◽  
Andrew Xiao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Protein Tyrosine Phosphatases ◽  
Histone H2a ◽  
Eyes Absent ◽  
Damage Repair ◽  
Damage Response

In mammalian cells, the DNA damage-related histone H2A variant H2A.X is characterized by a C-terminal tyrosyl residue, Tyr-142, which is phosphorylated by an atypical kinase, WSTF. The phosphorylation status of Tyr-142 in H2A.X has been shown to be an important regulator of the DNA damage response by controlling the formation of γH2A.X foci, which are platforms for recruiting molecules involved in DNA damage repair and signaling. In this work, we present evidence to support the identification of the Eyes Absent (EYA) phosphatases, protein-tyrosine phosphatases of the haloacid dehalogenase superfamily, as being responsible for dephosphorylating the C-terminal tyrosyl residue of histone H2A.X. We demonstrate that EYA2 and EYA3 displayed specificity for Tyr-142 of H2A.X in assays in vitro. Suppression of eya3 by RNA interference resulted in elevated basal phosphorylation and inhibited DNA damage-induced dephosphorylation of Tyr-142 of H2A.X in vivo. This study provides the first indication of a physiological substrate for the EYA phosphatases and suggests a novel role for these enzymes in regulation of the DNA damage response.

scholarly journals HPV16-E2 induces prophase arrest and activates the cellular DNA damage response in vitro and in precursor lesions of cervical carcinoma

Oncotarget ◽  
2015 ◽  
Vol 6 (33) ◽  
pp. 34979-34991 ◽  
Author(s):  
Yuezhen Xue ◽  
Shen Yon Toh ◽  
Pingping He ◽  
Thimothy Lim ◽  
Diana Lim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cervical Carcinoma ◽  
Precursor Lesions ◽  
Damage Response ◽  
Cellular Dna

In vitro activity of the flt3-inhibitor su5614 and standard cytotoxic agents in tumour cells from patients with wild type and mutated flt3 acute myeloid leukaemia

2005 ◽  
Vol 29 (9) ◽  
pp. 1079-1081 ◽  
Author(s):  
Anna Åleskog ◽  
Martin Höglund ◽  
Jenny Pettersson ◽  
Monica Hermansson ◽  
Rolf Larsson ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Tumour Cells ◽  
Cytotoxic Agents ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Wild Type ◽  
Flt3 Inhibitor ◽  
Acute Myeloid

scholarly journals In Vitro Biological Characterization of DCUN1D5 in DNA Damage Response

2012 ◽  
Vol 13 (8) ◽  
pp. 4157-4162 ◽  
Author(s):  
Wei Guo ◽  
Guo-Jun Li ◽  
Hong-Bo Xu ◽  
Jie-Shi Xie ◽  
Tai-Ping Shi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Biological Characterization ◽  
Damage Response
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