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      Poly(ADP-ribose) polymerase inhibitor induces accelerated senescence in irradiated breast cancer cells and tumors.

      Cancer research

      Animals, Benzimidazoles, pharmacology, Breast Neoplasms, drug therapy, enzymology, pathology, radiotherapy, Cell Aging, drug effects, radiation effects, Cell Growth Processes, Cell Line, Tumor, Combined Modality Therapy, Dose-Response Relationship, Radiation, Enzyme Inhibitors, Female, Green Fluorescent Proteins, analysis, genetics, metabolism, Humans, Infrared Rays, Intracellular Signaling Peptides and Proteins, Mice, Mice, Nude, Poly(ADP-ribose) Polymerases, antagonists & inhibitors, Recombinant Fusion Proteins, Xenograft Model Antitumor Assays

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          Abstract

          Persistent DNA double-strand breaks (DSB) may determine the antitumor effects of ionizing radiation (IR) by inducing apoptosis, necrosis, mitotic catastrophe, or permanent growth arrest. IR induces rapid modification of megabase chromatin domains surrounding DSBs via poly-ADP-ribosylation, phosphorylation, acetylation, and protein assembly. The dynamics of these IR-induced foci (IRIF) have been implicated in DNA damage signaling and DNA repair. As an IRIF reporter, we tracked the relocalization of green fluorescent protein fused to a chromatin binding domain of the checkpoint adapter protein 53BP1 after IR of breast cancer cells and tumors. To block DSB repair in breast cancer cells and tumors, we targeted poly(ADP-ribose) polymerase (PARP) with ABT-888 (veliparib), one of several PARP inhibitors currently in clinical trials. PARP inhibition markedly enhanced IRIF persistence and increased breast cancer cell senescence both in vitro and in vivo, arguing for targeting IRIF resolution as a novel therapeutic strategy.

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          Author and article information

          Journal
          20610628
          2912962
          10.1158/0008-5472.CAN-09-4224

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