Poly(ADP-ribose) polymerase inhibitor induces accelerated senescence in irradiated breast cancer cells and tumors.
Poly(ADP-ribose) polymerase inhibitor induces accelerated senescence in irradiated breast cancer cells and tumors.
复制标题
DOI：
10.1158/0008-5472.can-09-4224
复制
发表时间：
2010-08-01
期刊：
影响因子：
11.2
通讯作者：
Weichselbaum RR
中科院分区：
文献类型：
--
作者：
Efimova EV;Mauceri HJ;Golden DW;Labay E;Bindokas VP;Darga TE;Chakraborty C;Barreto-Andrade JC;Crawley C;Sutton HG;Kron SJ;Weichselbaum RR
持续性 DNA 双链断裂 (DSB) 可能通过诱导细胞凋亡、坏死、有丝分裂灾难或永久生长停滞来决定电离辐射 (IR) 的抗肿瘤作用。电离辐射 (IR) 通过聚 ADP 核糖基化、磷酸化、乙酰化和蛋白质组装，诱导双链断裂 (DSB) 周围百万碱基染色质结构域的快速修饰。这些电离辐射诱导灶 (IRIF) 的动力学与 DNA 损伤信号传导和 DNA 修复有关。作为 IRIF 报告基因，我们追踪了乳腺癌细胞和肿瘤 IR 后融合到检查点接头蛋白 53BP1 染色质结合域的 GFP 的重新定位。为了阻断乳腺癌细胞和肿瘤中的 DSB 修复，我们使用 ABT-888 (veliparib) 靶向聚 (ADP-核糖) 聚合酶，ABT-888 (veliparib) 是目前正在进行临床试验的几种 PARP 抑制剂之一。 PARP 抑制显着增强了 IRIF 的持久性，并在体外和体内增加了乳腺癌细胞的衰老，这表明将 IRIF 分辨率作为一种新的治疗策略。
Persistent DNA double strand breaks (DSBs) may determine the anti-tumor effects of ionizing radiation (IR) by inducing apoptosis, necrosis, mitotic catastrophe or permanent growth arrest. Ionizing radiation (IR) induces rapid modification of megabase chromatin domains surrounding double strand breaks (DSBs) via poly-ADP-ribosylation, phosphorylation, acetylation, and protein assembly. The dynamics of these ionizing radiation-induced foci (IRIF) have been implicated in DNA damage signaling and DNA repair. As an IRIF reporter, we tracked relocalization of GFP 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 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.