Response of fibroblast cultures from ataxia‐telangiectasia patients to reactive oxygen species generated during inflammatory reactions

Ward, Amanda J.; Olive, Peggy L.; Burr, Aaron; Rosin, Miriam P.

doi:10.1002/em.2850240205

Cited by 63 publications

(22 citation statements)

References 53 publications

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“…5B). We and others have noted that a deficiency in ATM does not affect initial DNA rejoining kinetics in the comet assay (36,37), although lack of ATM can cause misrejoining and an increase in residual damage (38). Cells deficient in other genes involved in homologous recombination, like RAD51, Bloom syndrome, and BRCA1, do not seem to rejoin breaks more slowly than repair-proficient cells (39 -41).…”

Section: Discussionmentioning

confidence: 94%

Radiosensitization by the Histone Deacetylase Inhibitor PCI-24781

Bañuelos¹,

Banáth²,

MacPhail³

et al. 2007

Clinical Cancer Research

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Purpose: PCI-24781is a novel broad spectrum histone deacetylase inhibitor that is currently in phase I clinical trials. The ability of PCI-24781to act as a radiation sensitizer and the mechanisms of radiosensitization were examined. Experimental Design: Exponentially growing human SiHa cervical and WiDr colon carcinoma cells were exposed to 0.1to 10 Amol/L PCI-24781in vitro for 2 to 20 h before irradiation and 0 to 4 h after irradiation. Single cells and sorted populations were analyzed for histone acetylation, H2AX phosphorylation, cell cycle distribution, apoptotic fraction, and clonogenic survival. Results: PCI-24781treatment for 4 h increased histone H3 acetylation and produced a modest increase in gH2AX but negligible cell killing or radiosensitization.Treatment for 24 h resulted in up to 80% cell kill and depletion of cells in S phase. Toxicity reached maximum levels at a drug concentration of f1 Amol/L, and cells in G 1 phase at the end of treatment were preferentially spared. A similar dose-modifying factor (DMF 0.1 = 1.5) was observed for SiHa cells exposed for 24 h at 0.1 to 3 Amol/L, and more radioresistant WiDr cells showed less sensitization (DMF 0.1 = 1.2). Limited radiosensitization and less killing were observed in noncycling human fibroblasts. Cell sorting experiments confirmed that depletion of S-phase cells was not a major mechanism of radiosensitization and that inner noncycling cells of SiHa spheroids could be sensitized by nontoxic doses. PCI-24781 pretreatment increased the fraction of cells with gH2AX foci 24 h after irradation but did not affect the initial rate of loss of radiation-induced gH2AX or the rate of rejoining of DNA double-strand breaks.Conclusions: PCI-24781 shows promise as a radiosensitizing agent that may compromise the accuracy of repair of radiation damage.

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Section: Discussionmentioning

confidence: 94%

Radiosensitization by the Histone Deacetylase Inhibitor PCI-24781

Bañuelos¹,

Banáth²,

MacPhail³

et al. 2007

Clinical Cancer Research

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“…We undertook this study for several reasons as follows. 1) ATM-deficient cells have been reported to be unusually sensitive to oxidants such as nitric oxide, superoxide, and hydrogen peroxide in colony-forming efficiency assays compared with normal cells (21,(23)(24)(25). 2) ATM-deficient cells re-synthesize glutathione unusually slowly after depletion with diethyl maleate (22).…”

Section: Thymine Glycol Formation Induced By T-butyl Hydroperoxide Trmentioning

confidence: 99%

The Ataxia telangiectasia Gene Product Is Required for Oxidative Stress-induced G1 and G2Checkpoint Function in Human Fibroblasts

Shackelford

Innes

Sieber

et al. 2001

Journal of Biological Chemistry

114

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Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neuronal degeneration accompanied by ataxia, telangiectasias, acute cancer predisposition, and sensitivity to ionizing radiation (IR). Cells from individuals with AT show unusual sensitivity to IR, severely attenuated cell cycle checkpoint functions, and poor p53 induction in response to IR compared with normal human fibroblasts (NHFs). The gene mutated in AT (ATM) has been cloned, and its product, pATM, has IR-inducible kinase activity. The AT phenotype has been suggested to be a consequence, at least in part, of an inability to respond appropriately to oxidative damage. To test this hypothesis, we examined the ability of NHFs and AT dermal fibroblasts to respond to t-butyl hydroperoxide and IR treatment. AT fibroblasts exhibit, in comparison to NHFs, increased sensitivity to the toxicity of t-butyl hydroperoxide, as measured by colony-forming efficiency assays. Unlike NHFs, AT fibroblasts fail to show G 1 and G 2 phase checkpoint functions or to induce p53 in response to t-butyl hydroperoxide. Treatment of NHFs with t-butyl hydroperoxide activates pATM-associated kinase activity. Our results indicate that pATM is involved in responding to certain aspects of oxidative damage and in signaling this information to downstream effectors of the cell cycle checkpoint functions. Our data further suggest that some of the pathologies seen in AT could arise as a consequence of an inability to respond normally to oxidative damage.

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“…This finding had clear implications of ATM in redox signalling pathway. This led to further in vitro investigations in the coming years that attempted to discern ATM functioning in oxidative stress response which supported ATM's role in these domains [182,183]. In another report, study of the anti-oxidant capacity of ten A-T patients as compared to age matched controls showed a reduced antioxidant capacity and altered levels of reactive oxygen species (ROS) scavenging enzymes [184].…”

Section: Beyond Dna Damage Repair: Atm's Role In Oxidative Stress Andmentioning

confidence: 97%

ATM in focus: A damage sensor and cancer target

Khalil¹,

Tummala²,

Zhelev³

2012

Biodiscovery

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The ability of a cell to conserve and maintain its native DNA sequence is fundamental for the survival and normal functioning of the whole organism and protection from cancer development. Here we review recently obtained results and current topics concerning the role of the ataxia-telangiectasia mutated (ATM) protein kinase as a damage sensor and its potential as therapeutic target for treating cancer. This monograph discusses DNA repair mechanisms activated after DNA doublestrand breaks (DSBs), i.e. non-homologous end joining, homologous recombination and single strand annealing and the role of ATM in the above types of repair. In addition to DNA repair, ATM participates in a diverse set of physiological processes involving metabolic regulation, oxidative stress, transcriptional modulation, protein degradation and cell proliferation. Full understanding of the complexity of ATM functions and the design of therapeutics that modulate its activity to combat diseases such as cancer necessitates parallel theoretical and experimental efforts. This could be best addressed by employing a systems biology approach, involving mathematical modelling of cell signalling pathways.

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Response of fibroblast cultures from ataxia‐telangiectasia patients to reactive oxygen species generated during inflammatory reactions

Cited by 63 publications

References 53 publications

Radiosensitization by the Histone Deacetylase Inhibitor PCI-24781

Radiosensitization by the Histone Deacetylase Inhibitor PCI-24781

The Ataxia telangiectasia Gene Product Is Required for Oxidative Stress-induced G1 and G2Checkpoint Function in Human Fibroblasts

ATM in focus: A damage sensor and cancer target

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