Article

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

Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois 60637, USA.
Cancer Research (impact factor: 7.86). 08/2010; 70(15):6277-82. DOI:10.1158/0008-5472.CAN-09-4224 pp.6277-82
Source: PubMed

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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Keywords

antitumor effects
 
breast cancer cell senescence
 
breast cancer cells
 
checkpoint adapter protein 53BP1
 
chromatin binding domain
 
DNA damage signaling
 
green fluorescent protein fused
 
inducing apoptosis
 
IR induces rapid modification
 
IR-induced foci
 
IRIF persistence
 
IRIF reporter
 
IRIF resolution
 
megabase chromatin domains
 
mitotic catastrophe
 
novel therapeutic strategy
 
PARP inhibitors
 
permanent growth arrest
 
Persistent DNA double-strand breaks
 
protein assembly