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Article ; Online: Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models.

Rodriguez-Berriguete, Gonzalo / Puliyadi, Rathi / Machado, Nicole / Barberis, Alessandro / Prevo, Remko / McLaughlin, Martin / Buffa, Francesca M / Harrington, Kevin J / Higgins, Geoff S

Cell death & disease

2024 Volume 15, Issue 1, Page(s) 32

Abstract: Immune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells. However, a substantial number of patients treated with ICB develop relapse or do not ... ...

Abstract	Immune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells. However, a substantial number of patients treated with ICB develop relapse or do not respond, which has been partly attributed to the immune-suppressive effect of tumour hypoxia. We have previously demonstrated that the mitochondrial complex III inhibitor atovaquone alleviates tumour hypoxia both in human xenografts and in cancer patients by decreasing oxygen consumption and consequently increasing oxygen availability in the tumour. Here, we show that atovaquone alleviates hypoxia and synergises with the ICB antibody anti-PD-L1, significantly improving the rates of tumour eradication in the syngeneic CT26 model of colorectal cancer. The synergistic effect between atovaquone and anti-PD-L1 relied on CD8+ T cells, resulted in the establishment of a tumour-specific memory immune response, and was not associated with any toxicity. We also tested atovaquone in combination with anti-PD-L1 in the LLC (lung) and MC38 (colorectal) cancer syngeneic models but, despite causing a considerable reduction in tumour hypoxia, atovaquone did not add any therapeutic benefit to ICB in these models. These results suggest that atovaquone has the potential to improve the outcomes of patients treated with ICB, but predictive biomarkers are required to identify individuals likely to benefit from this intervention.
MeSH term(s)	Humans ; Animals ; Mice ; Atovaquone/pharmacology ; Atovaquone/therapeutic use ; Electron Transport Complex III ; Neoplasms/drug therapy ; CD8-Positive T-Lymphocytes ; Immunotherapy/methods ; B7-H1 Antigen ; Tumor Microenvironment
Chemical Substances	Atovaquone (Y883P1Z2LT) ; Electron Transport Complex III (EC 7.1.1.8) ; B7-H1 Antigen
Language	English
Publishing date	2024-01-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-023-06405-8
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Article ; Online: Targeting TOPK sensitises tumour cells to radiation-induced damage by enhancing replication stress.

Herbert, Katharine J / Puliyadi, Rathi / Prevo, Remko / Rodriguez-Berriguete, Gonzalo / Ryan, Anderson / Ramadan, Kristijan / Higgins, Geoff S

Cell death and differentiation

2020 Volume 28, Issue 4, Page(s) 1333–1346

Abstract: T-LAK-originated protein kinase (TOPK) overexpression is a feature of multiple cancers, yet is absent from most phenotypically normal tissues. As such, TOPK expression profiling and the development of TOPK-targeting pharmaceutical agents have raised ... ...

Abstract	T-LAK-originated protein kinase (TOPK) overexpression is a feature of multiple cancers, yet is absent from most phenotypically normal tissues. As such, TOPK expression profiling and the development of TOPK-targeting pharmaceutical agents have raised hopes for its future potential in the development of targeted therapeutics. Results presented in this paper confirm the value of TOPK as a potential target for the treatment of solid tumours, and demonstrate the efficacy of a TOPK inhibitor (OTS964) when used in combination with radiation treatment. Using H460 and Calu-6 lung cancer xenograft models, we show that pharmaceutical inhibition of TOPK potentiates the efficacy of fractionated irradiation. Furthermore, we provide in vitro evidence that TOPK plays a hitherto unknown role during S phase, showing that TOPK depletion increases fork stalling and collapse under conditions of replication stress and exogenous DNA damage. Transient knockdown of TOPK was shown to impair recovery from fork stalling and to increase the formation of replication-associated single-stranded DNA foci in H460 lung cancer cells. We also show that TOPK interacts directly with CHK1 and Cdc25c, two key players in the checkpoint signalling pathway activated after replication fork collapse. This study thus provides novel insights into the mechanism by which TOPK activity supports the survival of cancer cells, facilitating checkpoint signalling in response to replication stress and DNA damage.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Apoptosis/radiation effects ; Cell Line, Tumor ; Checkpoint Kinase 1/drug effects ; Checkpoint Kinase 1/genetics ; Checkpoint Kinase 1/radiation effects ; Female ; Humans ; Lung Neoplasms/metabolism ; Lung Neoplasms/radiotherapy ; Mice ; Mice, Nude ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Mitogen-Activated Protein Kinase Kinases/genetics ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Protein Kinase Inhibitors/pharmacology ; Quinolones/pharmacology ; Radiation Tolerance/drug effects ; Radiation Tolerance/genetics ; Signal Transduction ; Survival Rate ; Xenograft Model Antitumor Assays ; cdc25 Phosphatases/drug effects ; cdc25 Phosphatases/genetics ; cdc25 Phosphatases/radiation effects
Chemical Substances	OTS964 ; Protein Kinase Inhibitors ; Quinolones ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2) ; PDZ-binding kinase (EC 2.7.12.2) ; CDC25C protein, human (EC 3.1.3.48) ; cdc25 Phosphatases (EC 3.1.3.48)
Language	English
Publishing date	2020-11-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-020-00655-1
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Zs.A 4230: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models.

Rodriguez-Berriguete, Gonzalo / Ranzani, Marco / Prevo, Remko / Puliyadi, Rathi / Machado, Nicole / Bolland, Hannah R / Millar, Val / Ebner, Daniel / Boursier, Marie / Cerutti, Aurora / Cicconi, Alessandro / Galbiati, Alessandro / Grande, Diego / Grinkevich, Vera / Majithiya, Jayesh B / Piscitello, Desiree / Rajendra, Eeson / Stockley, Martin L / Boulton, Simon J /

Hammond, Ester M / Heald, Robert A / Smith, Graeme C M / Robinson, Helen M R / Higgins, Geoff S

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Volume 29, Issue 8, Page(s) 1631–1642

Abstract: Purpose: DNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, ... ...

Abstract	Purpose: DNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In this study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy. Experimental design: We characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo. Results: Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, noncancerous cells were not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared with radiation alone. Conclusions: These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy.
MeSH term(s)	Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/radiotherapy ; Cell Line, Tumor
Language	English
Publishing date	2023-01-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-2977
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Zs.A 4223: Show issues

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Article ; Online: The protease SPRTN and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability.

Ruggiano, Annamaria / Vaz, Bruno / Kilgas, Susan / Popović, Marta / Rodriguez-Berriguete, Gonzalo / Singh, Abhay N / Higgins, Geoff S / Kiltie, Anne E / Ramadan, Kristijan

Cell reports

2021 Volume 37, Issue 10, Page(s) 110080

Abstract: DNA-protein crosslinks (DPCs) are a specific type of DNA lesion in which proteins are covalently attached to DNA. Unrepaired DPCs lead to genomic instability, cancer, neurodegeneration, and accelerated aging. DPC proteolysis was recently identified as a ... ...

Abstract	DNA-protein crosslinks (DPCs) are a specific type of DNA lesion in which proteins are covalently attached to DNA. Unrepaired DPCs lead to genomic instability, cancer, neurodegeneration, and accelerated aging. DPC proteolysis was recently identified as a specialized pathway for DPC repair. The DNA-dependent protease SPRTN and the 26S proteasome emerged as two independent proteolytic systems. DPCs are also repaired by homologous recombination (HR), a canonical DNA repair pathway. While studying the cellular response to DPC formation, we identify ubiquitylation and SUMOylation as two major signaling events in DNA replication-coupled DPC repair. DPC ubiquitylation recruits SPRTN to repair sites, promoting DPC removal. DPC SUMOylation prevents DNA double-strand break formation, HR activation, and potentially deleterious genomic rearrangements. In this way, SUMOylation channels DPC repair toward SPRTN proteolysis, which is a safer pathway choice for DPC repair and prevention of genomic instability.
MeSH term(s)	DNA Breaks, Double-Stranded ; DNA Damage ; DNA Repair ; DNA Replication ; DNA, Neoplasm/biosynthesis ; DNA, Neoplasm/genetics ; DNA, Neoplasm/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Female ; Genomic Instability ; HEK293 Cells ; HeLa Cells ; Homologous Recombination ; Humans ; Male ; Proteolysis ; Sumoylation ; Synthetic Lethal Mutations
Chemical Substances	DNA, Neoplasm ; DNA-Binding Proteins ; SPRTN protein, human
Language	English
Publishing date	2021-12-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2021.110080
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Article ; Online: Epidermal growth factor induces p38 MAPK-dependent G0/G1-to-S transition in prostate cancer cells upon androgen deprivation conditions.

Rodríguez-Berriguete, Gonzalo / Torrealba, Norelia / Fraile, Benito / Paniagua, Ricardo / Royuela, Mar

Growth factors (Chur, Switzerland)

2016 Volume 34, Issue 1-2, Page(s) 5–10

Abstract: Epidermal growth factor (EGF) is thought to contribute to the emergence of castration-resistant (CR) prostate tumors by inducing proliferation of cancer cells despite the low levels of circulating androgens achieved by androgen deprivation therapy. We ... ...

Abstract	Epidermal growth factor (EGF) is thought to contribute to the emergence of castration-resistant (CR) prostate tumors by inducing proliferation of cancer cells despite the low levels of circulating androgens achieved by androgen deprivation therapy. We show that, in LNCaP cells, androgen deprivation induces arrest in the G0/G1 cell cycle phase, and that EGF partially rescues this arrest without affecting cell death. Inhibition of p38 MAPK, but not MEK or IKK-β, completely abrogates the EGF-induced proliferation of LNCaP cells in androgen-depleted medium, and decreases the fraction of G0/G1-arrested cells. Our results suggest that EGF enables prostate cancer cells to overcome the growth restriction imposed by androgen deprivation by stimulating G0/G1-to-S transition via p38 MAPK. These results suggest the potential of developing therapies for advanced prostate cancer that block the G0/G1 to S transition, such as by targeting p38 MAPK, or that aim to induce apoptosis in G0/G1-arrested cancer cells.
Language	English
Publishing date	2016-02
Publishing country	England
Document type	Journal Article
ZDB-ID	1035755-5
ISSN	1029-2292 ; 0897-7194
ISSN (online)	1029-2292
ISSN	0897-7194
DOI	10.3109/08977194.2015.1132712
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Zs.A 2612: Show issues

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Article ; Online: PI3K pathway and Bcl-2 family. Clinicopathological features in prostate cancer.

Torrealba, Norelia / Rodriguez-Berriguete, Gonzalo / Fraile, Benito / Olmedilla, Gabriel / Martínez-Onsurbe, Pilar / Sánchez-Chapado, Manuel / Paniagua, Ricardo / Royuela, Mar

The aging male : the official journal of the International Society for the Study of the Aging Male

2018 Volume 21, Issue 3, Page(s) 211–222

Abstract: The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathways and Bcl-2 family play a central role in prostate cancer (PC). The aim was to determine influence in the biochemical progression in PC. To evaluate the association between clinic pathological and ... ...

Abstract	The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathways and Bcl-2 family play a central role in prostate cancer (PC). The aim was to determine influence in the biochemical progression in PC. To evaluate the association between clinic pathological and immunohistochemical variables, Spearman's test was performed. Log-rank test and Kaplan-Meier curves were used for survival comparisons. To explore the correlation of the studied immunohistochemical parameters and the established prognostic variables with biochemical progression, univariate and multivariate Cox proportional Hazard regression analyses were performed. Spearman analysis showed correlation between stroma expression and tumor expression of PI3K with biochemical progression (p = .009, p = .004), respectively, and tumor immunohistochemical score with biochemical progression (p = .051). In the multivariate Cox regression model, only PI3K was retained as independent predictors of biochemical progression. In stroma expression, PI3K is (HR 0.172, 95% CI 0.065-0.452, p = .000); tumor expression, PI3K is (HR 0.087, 95% CI 0.026-0.293, p = .000), and tumor immunohistochemical score (HR 0.382, 95% CI 0.209-0.697 p = .002). Our results suggest a role for prostatic expression of PI3K was prognostic markers for PC. PI3K/AKT/mTOR and Bcl-2 family are becoming an important therapeutic target and predictive biomarkers of onset and progression of PC.
MeSH term(s)	Aged ; Biomarkers, Tumor ; Case-Control Studies ; Disease Progression ; Humans ; Kaplan-Meier Estimate ; Longitudinal Studies ; Male ; Middle Aged ; Phosphatidylinositol 3-Kinase/blood ; Phosphatidylinositol 3-Kinase/metabolism ; Proportional Hazards Models ; Prostate-Specific Antigen/blood ; Prostate-Specific Antigen/metabolism ; Prostatic Neoplasms/blood ; Prostatic Neoplasms/diagnosis ; Prostatic Neoplasms/pathology ; bcl-2 Homologous Antagonist-Killer Protein/blood ; bcl-2 Homologous Antagonist-Killer Protein/metabolism
Chemical Substances	Biomarkers, Tumor ; bcl-2 Homologous Antagonist-Killer Protein ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; Prostate-Specific Antigen (EC 3.4.21.77)
Language	English
Publishing date	2018-01-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2108146-3
ISSN	1473-0790 ; 1368-5538
ISSN (online)	1473-0790
ISSN	1368-5538
DOI	10.1080/13685538.2018.1424130
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Zs.A 5776: Show issues

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Article: The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress.

Coates, James T T / Rodriguez-Berriguete, Gonzalo / Puliyadi, Rathi / Ashton, Thomas / Prevo, Remko / Wing, Archie / Granata, Giovanna / Pirovano, Giacomo / McKenna, Gillies W / Higgins, Geoff S

Cell death discovery

2020 Volume 6, Page(s) 110

Abstract: Platinum chemotherapies are highly effective cytotoxic agents but often induce resistance when used as monotherapies. Combinatorial strategies limit this risk and provide effective treatment options for many cancers. Here, we repurpose atovaquone (ATQ), ... ...

Abstract	Platinum chemotherapies are highly effective cytotoxic agents but often induce resistance when used as monotherapies. Combinatorial strategies limit this risk and provide effective treatment options for many cancers. Here, we repurpose atovaquone (ATQ), a well-tolerated & FDA-approved anti-malarial agent by demonstrating that it potentiates cancer cell death of a subset of platinums. We show that ATQ in combination with carboplatin or cisplatin induces striking and repeatable concentration- and time-dependent cell death sensitization in vitro across a variety of cancer cell lines. ATQ induces mitochondrial reactive oxygen species (mROS), depleting intracellular glutathione (GSH) pools in a concentration-dependent manner. The superoxide dismutase mimetic MnTBAP rescues ATQ-induced mROS production and pre-loading cells with the GSH prodrug N-acetyl cysteine (NAC) abrogates the sensitization. Together, these findings implicate ATQ-induced oxidative stress as key mediator of the sensitizing effect. At physiologically achievable concentrations, ATQ and carboplatin furthermore synergistically delay the growth of three-dimensional avascular spheroids. Clinically, ATQ is a safe and specific inhibitor of the electron transport chain (ETC) and is concurrently being repurposed as a candidate tumor hypoxia modifier. Together, these findings suggest that ATQ is deserving of further study as a candidate platinum sensitizing agent.
Language	English
Publishing date	2020-10-27
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/s41420-020-00343-6
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Article ; Online: Expression of several cytokines in prostate cancer: Correlation with clinical variables of patients. Relationship with biochemical progression of the malignance.

Torrealba, Norelia / Rodríguez-Berriguete, Gonzalo / Fraile, Benito / Olmedilla, Gabriel / Martínez-Onsurbe, Pilar / Guil-Cid, Manuel / Paniagua, Ricardo / Royuela, Mar

Cytokine

2017 Volume 89, Page(s) 105–115

Abstract: Background: This work is focused on finding new markers that complement or diagnoses currently used towards improving knowledge histological and statistical aspects that allow us to predict the local stage carcinomas and to identify and understand all ... ...

Abstract	Background: This work is focused on finding new markers that complement or diagnoses currently used towards improving knowledge histological and statistical aspects that allow us to predict the local stage carcinomas and to identify and understand all the factors related to the progression of this disease. Materials and methods: Prostates were obtained from: normal prostates from 20 men, diagnosis of BPH (Benign Prostatic Hyperplasia) from 35 men and prostate cancer from 86 men. We studied the behavior of cytokines that have been implicated in inflammatory processes: TNF-alfa, IL-6, IL-1, EGF and TGF-B. Expression of these cytokines and its receptors was analyzed by immunohistochemistry. Spearman's test, Kaplan-Meier curves, univariate and multivariate Cox proportional hazard regression analyses were performed. Results: Spearman's analysis showed that there was at least one correlation between TGFB-B, IL-6, gp-130, IL-1B, IL-1R, IL-1RII and clinic pathological feature (preoperative serum PSA, clinical t stage, pathological t stage, positive surgical margins, biochemical progression, survival). Immunostaining score was correlated with some of the clinicopathological feature. In Cox multivariate analysis between the prognostic variables (pathological T stage, Gleason score and lymph node) and immunohistochemical parameters (TGF-B, IL-1a, intensity TGFBRI and intensity TGFBRII) only the expression of IL-1a was retained as independent predictors of biochemical progression after radical prostatectomy. Conclusions: Our results suggest a role for prostatic expression of TGF-B, IL-1a, TGFBRI and TGFBRII as prognostic markers for prostate cancer. The rational combination of novel agents directed toward the inactivation of TGF-B, IL-1a, TGFBRI and TGFBRII could disrupt complementary tumor cell proliferation pathways.
Language	English
Publishing date	2017-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1018055-2
ISSN	1096-0023 ; 1043-4666
ISSN (online)	1096-0023
ISSN	1043-4666
DOI	10.1016/j.cyto.2016.08.008
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Zs.A 2840: Show issues

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Article: External Beam Radiation Therapy and Enadenotucirev: Inhibition of the DDR and Mechanisms of Radiation-Mediated Virus Increase.

Pokrovska, Tzveta D / Jacobus, Egon J / Puliyadi, Rathi / Prevo, Remko / Frost, Sally / Dyer, Arthur / Baugh, Richard / Rodriguez-Berriguete, Gonzalo / Fisher, Kerry / Granata, Giovanna / Herbert, Katharine / Taverner, William K / Champion, Brian R / Higgins, Geoff S / Seymour, Len W / Lei-Rossmann, Janet

Cancers

2020 Volume 12, Issue 4

Abstract: Ionising radiation causes cell death through the induction of DNA damage, particularly double-stranded DNA (dsDNA) breaks. Evidence suggests that adenoviruses inhibit proteins involved in the DNA damage response (DDR) to prevent recognition of double- ... ...

Abstract	Ionising radiation causes cell death through the induction of DNA damage, particularly double-stranded DNA (dsDNA) breaks. Evidence suggests that adenoviruses inhibit proteins involved in the DNA damage response (DDR) to prevent recognition of double-stranded viral DNA genomes as cellular dsDNA breaks. We hypothesise that combining adenovirus treatment with radiotherapy has the potential for enhancing tumour-specific cytotoxicity through inhibition of the DDR and augmentation of virus production. We show that EnAd, an Ad3/Ad11p chimeric oncolytic adenovirus currently being trialled in colorectal and other cancers, targets the DDR pathway at a number of junctures. Infection is associated with a decrease in irradiation-induced 53BP1 and Rad51 foci formation, and in total DNA ligase IV levels. We also demonstrate a radiation-associated increase in EnAd production in vitro and in a pilot in vivo experiment. Given the current limitations of in vitro techniques in assessing for synergy between these treatments, we adapted the plaque assay to allow monitoring of viral plaque size and growth and utilised the xCELLigence cell adhesion assay to measure cytotoxicity. Our study provides further evidence on the interaction between adenovirus and radiation in vitro and in vivo and suggests these have at least an additive, and possibly a synergistic, impact on cytotoxicity.
Language	English
Publishing date	2020-03-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12040798
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Article ; Online: Nucleoporin 54 contributes to homologous recombination repair and post-replicative DNA integrity.

Rodriguez-Berriguete, Gonzalo / Granata, Giovanna / Puliyadi, Rathi / Tiwana, Gaganpreet / Prevo, Remko / Wilson, Rhodri S / Yu, Sheng / Buffa, Francesca / Humphrey, Timothy C / McKenna, W Gillies / Higgins, Geoff S

Nucleic acids research

2018 Volume 46, Issue 15, Page(s) 7731–7746

Abstract: The nuclear pore complex (NPC) machinery is emerging as an important determinant in the maintenance of genome integrity and sensitivity to DNA double-strand break (DSB)-inducing agents, such as ionising radiation (IR). In this study, using a high- ... ...

Abstract	The nuclear pore complex (NPC) machinery is emerging as an important determinant in the maintenance of genome integrity and sensitivity to DNA double-strand break (DSB)-inducing agents, such as ionising radiation (IR). In this study, using a high-throughput siRNA screen, we identified the central channel NPC protein Nup54, and concomitantly its molecular partners Nup62 and Nup58, as novel factors implicated in radiosensitivity. Nup54 depletion caused an increase in cell death by mitotic catastrophe after IR, and specifically enhanced both the duration of the G2 arrest and the radiosensitivity of cells that contained replicated DNA at the time of IR exposure. Nup54-depleted cells also exhibited increased formation of chromosome aberrations arisen from replicated DNA. Interestingly, we found that Nup54 is epistatic with the homologous recombination (HR) factor Rad51. Moreover, using specific DNA damage repair reporters, we observed a decreased HR repair activity upon Nup54 knockdown. In agreement with a role in HR repair, we also demonstrated a decreased formation of HR-linked DNA synthesis foci and sister chromatid exchanges after IR in cells depleted of Nup54. Our study reveals a novel role for Nup54 in the response to IR and the maintenance of HR-mediated genome integrity.
MeSH term(s)	Cell Line, Tumor ; Cell Survival/genetics ; Cell Survival/radiation effects ; DNA/genetics ; DNA/metabolism ; DNA Breaks, Double-Stranded/radiation effects ; DNA Replication ; HeLa Cells ; Humans ; MCF-7 Cells ; Nuclear Pore/genetics ; Nuclear Pore/metabolism ; Nuclear Pore Complex Proteins/genetics ; Nuclear Pore Complex Proteins/metabolism ; RNA Interference ; Rad51 Recombinase/genetics ; Rad51 Recombinase/metabolism ; Radiation, Ionizing ; Recombinational DNA Repair ; Sister Chromatid Exchange/radiation effects
Chemical Substances	NUP54 protein, human ; Nuclear Pore Complex Proteins ; DNA (9007-49-2) ; Rad51 Recombinase (EC 2.7.7.-)
Language	English
Publishing date	2018-07-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gky569
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