Abstract
The aim of this study was to assess niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase (PARP) inhibitor, for its ability to radiosensitize human tumor cells. Human tumor cells derived from lung, breast and prostate cancers were tested for radiosensitization by niraparib using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of niraparib to alter the repair of radiation-induced DNA double strand breaks (DSBs) was determined using detection of γ-H2AX foci and RAD51 foci. Clonogenic survival analyses indicated that micromolar concentrations of niraparib radiosensitized tumor cell lines derived from lung, breast, and prostate cancers independently of their p53 status but not cell lines derived from normal tissues. Niraparib also sensitized tumor cells to H2O2 and converted H2O2-induced single strand breaks (SSBs) into DSBs during DNA replication. These results indicate that human tumor cells are significantly radiosensitized by the potent and selective PARP-1 inhibitor, niraparib, in the in vitro setting. The mechanism of this effect appears to involve a conversion of sublethal SSBs into lethal DSBs during DNA replication due to the inhibition of base excision repair by the drug. Taken together, our findings strongly support the clinical evaluation of niraparib in combination with radiation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / radiation effects
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DNA Breaks, Double-Stranded / drug effects
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DNA Breaks, Double-Stranded / radiation effects
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DNA Breaks, Single-Stranded / drug effects
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DNA Breaks, Single-Stranded / radiation effects
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DNA Repair / drug effects
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DNA Repair / radiation effects
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Female
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Histones / metabolism
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Humans
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Hydrogen Peroxide / pharmacology
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Indazoles / pharmacology*
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Male
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Microscopy, Fluorescence
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Oxidants / pharmacology
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Piperidines / pharmacology*
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Poly(ADP-ribose) Polymerase Inhibitors*
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Poly(ADP-ribose) Polymerases / metabolism
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Rad51 Recombinase / metabolism
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Radiation-Sensitizing Agents / pharmacology*
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Tumor Stem Cell Assay
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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H2AX protein, human
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Histones
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Indazoles
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Oxidants
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Piperidines
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Poly(ADP-ribose) Polymerase Inhibitors
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Radiation-Sensitizing Agents
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Tumor Suppressor Protein p53
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Hydrogen Peroxide
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Poly(ADP-ribose) Polymerases
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Rad51 Recombinase
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niraparib