A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia

Liu, Stanley K.; Coackley, Carla; Krause, Mechthild; Jalali, Farid; Chan, Norman; Bristow, Robert G.

doi:10.1016/j.radonc.2008.04.005

Cited by 128 publications

(92 citation statements)

References 49 publications

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“…To date, no targeted protocol has been developed for the treatment of triple-negative breast cancer. Although studies show that parp1 (poly[ADP-ribose] polymerase-1) inhibitor can potentially increase the sensitivity of triple-negative breast cancer to radiotherapy 17,18 , treatment of triple-negative breast cancer with parp1 inhibitor and irradiation is still in its infancy.…”

Section: Discussionmentioning

confidence: 99%

“…Some investigators experimented with altering the patterns of radiotherapy in breast cancer patients with a high risk of lrr, applying targeted biologic therapy 6,[16][17][18] and an increase in the radiation dose. Panoff et al 22 used chest irradiation at the recommended dose of more than 50 Gy and found that the 5-year lrr rate was 5.7% for patients receiving a radiation dose of more than 50.4 Gy (median: 60.4 Gy) and 12.7% for those receiving 50.4 Gy or less (median: 50.4 Gy, p = 0.054).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Risk Factors for Locoregional Recurrence After Postmastectomy Radiotherapy in Breast Cancer Patients with Four or More Positive Axillary Lymph Nodes

Zhou

et al. 2014

Current Oncology

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Risk Factors for Locoregional Recurrence After Postmastectomy Radiotherapy in Breast Cancer Patients with Four or More Positive Axillary Lymph Nodes

Zhou

et al. 2014

Current Oncology

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“…In this model, the exogenous DNA damage created by ionizing radiation can be studied without the bias from endogenous DNA damage created during DNA replication in the S phase of the cell cycle (Al Rashid et al, 2005). Furthermore, the induction of c-H2AX, or other DNA damage sensor foci, which occur as a result of replicative breaks or chromatin compaction in the S and G2 phases of the cell cycle, respectively, can be avoided (Liu et al, 2008).…”

Section: G0-g1 Synchronized Fibroblasts Represent a Robust Model To Smentioning

confidence: 99%

Chronic hypoxia compromises repair of DNA double-strand breaks to drive genetic instability

Kumareswaran

Ludkovski

Meng

et al. 2012

Journal of Cell Science

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112

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SummaryHypoxic cells have been linked to genetic instability and tumor progression. However, little is known about the exact relationship between DNA repair and genetic instability in hypoxic cells. We therefore tested whether the sensing and repair of DNA double-strand breaks (DNA-dsbs) is altered in irradiated cells kept under continual oxic, hypoxic or anoxic conditions. Synchronized G0-G1 human fibroblasts were irradiated (0-10 Gy) after initial gassing with 0% O 2 (anoxia), 0.2% O 2 (hypoxia) or 21% O 2 (oxia) for 16 hours. The response of phosphorylated histone H2AX (c-H2AX), phosphorylated ataxia telangiectasia mutated [ATM(Ser1981)], and the p53 binding protein 1 (53BP1) was quantified by intranuclear DNA repair foci and western blotting. At 24 hours following DNA damage, residual c-H2AX, ATM(Ser1981) and 53BP1 foci were observed in hypoxic cells. This increase in residual DNA-dsbs under hypoxic conditions was confirmed using neutral comet assays. Clonogenic survival was also reduced in chronically hypoxic cells, which is consistent with the observation of elevated G1-associated residual DNA-dsbs. We also observed an increase in the frequency of chromosomal aberrations in chronically hypoxic cells. We conclude that DNA repair under continued hypoxia leads to decreased repair of G1-associated DNA-dsbs, resulting in increased chromosomal instability. Our findings suggest that aberrant DNA-dsb repair under hypoxia is a potential factor in hypoxia-mediated genetic instability.Key words: DNA double-strand breaks, hypoxia, non-homologous end joining, DNA double-strand break sensors, c-H2AX, genetic instability Introduction Human cells have evolved specific pathways to repair DNA double-strand breaks (DNA-dsbs) and enact cell cycle checkpoints following DNA damage to ensure genetic stability. These pathways could be oxygen sensitive because endogenous and exogenous DNA damage can be differentially processed and repaired in oxic versus hypoxic cells Bristow and Hill, 2008). For example, intratumoral hypoxia can drive genetic instability and accelerate tumor progression. It can also lead to altered radio-or chemoresistance, enhanced mutagenesis, impaired DNA repair and increased systemic metastasis (reviewed by Bindra et al., 2007;Bristow and Hill, 2008;Huang et al., 2007). The consequence of hypoxic exposure on DNA damage response (DDR) sensing and signalling might relate, in part, to the oxygen level (e.g. hypoxia or anoxia) and the duration of the hypoxic exposure (acute or cycling hypoxia versus chronic or prolonged hypoxia).One of the most lethal DNA lesions is a DNA-dsb. Incorrectly or non-repaired DNA-dsbs could result in chromosomal deletions, amplifications, aneuploidy and genetic instability (Helleday et al., 2007). Despite the fact that the vast majority of human tumors contain hypoxic sub-regions, little is known about the potential effects of continual hypoxia on DNA-dsb sensing and processing. The signal transduction processes in response to DNA-dsbs are dependent on the kinase activity and autophos...

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“…Briefly, cells were lysed and incubated for 5 min on ice in cytoplasmic buffer [25 . The nuclei were lysed by vigorous pipetting, incubated on ice for 15 min, and then centrifuged at 3,000 rpm for 5 min.…”

Section: Cell Culture Conditionsmentioning

confidence: 99%

“…In vivo Studies To derive PC3 prostate xenografts for in vivo growth delay studies of combined treatments with imatinib and radiotherapy (IR), male BALB/c nude mice were injected s. (25).…”

Section: Assay For Homologous Recombination and Rad51 Sirna Treatmentsmentioning

confidence: 99%

Targeting homologous recombination using imatinib results in enhanced tumor cell chemosensitivity and radiosensitivity

Choudhury

Zhao

Jalali

et al. 2009

Molecular Cancer Therapeutics

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RAD51 is a key protein in the homologous recombination (HR) pathway of DNA double-strand break repair, and HR represents a novel target for cancer therapy. Because imatinib (Gleevec) has been reported to reduce RAD51 protein levels, we tested the clonogenic survival for RT112, H1299, PANC1, and PC3 tumor cell lines of varying p53 status and normal GM05757 normal fibroblasts after exposure to single agent imatinib (0 -20 Mmol/ L; 0 -72 hours). We also combined imatinib with DNA damaging agents that are toxic to RAD51-deficient cells, including ionizing radiation, gemcitabine, and mitomycin C. We observed decreased nuclear expression and chromatin binding of RAD51 protein following imatinib treatment. Imatinib also resulted in decreased error-free HR as determined by a flow cytometry -based integrated direct repeat-green fusion protein reporter system; this correlated to reduced RAD51 expression. Clonogenic survival experiments revealed increased cell kill for imatinib-treated cells in combination with ionizing radiation, gemcitabine, and mitomycin C, due in part to mitotic catastrophe. In experiments using imatinib and gemcitabine, tumor cell lines were sensitized to a greater extent than normal fibroblasts. This preservation of the therapeutic ratio was confirmed in vivo using PC3 xenograft growth delay and intestinal crypt cell clonogenic assays. HR inhibition may be an additional mechanism of action for the chemosensitization and radiosensitization of solid tumors with imatinib with preservation of the therapeutic ratio.

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A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia

Cited by 128 publications

References 49 publications

Risk Factors for Locoregional Recurrence After Postmastectomy Radiotherapy in Breast Cancer Patients with Four or More Positive Axillary Lymph Nodes

Risk Factors for Locoregional Recurrence After Postmastectomy Radiotherapy in Breast Cancer Patients with Four or More Positive Axillary Lymph Nodes

Chronic hypoxia compromises repair of DNA double-strand breaks to drive genetic instability

Targeting homologous recombination using imatinib results in enhanced tumor cell chemosensitivity and radiosensitivity

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