Inhibition of poly (ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models
Inhibition of poly (ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models
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DOI：
10.1158/1078-0432.ccr-06-2872
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发表时间：
2007-05-15
影响因子：
11.5
通讯作者：
Lu, Bo
中科院分区：
文献类型：
--
作者：
Albert, Jeffrey M.;Cao, Carolyn;Lu, Bo
目的：聚（ADP-核糖）聚合酶-1（RARP-1）是催化ADP-核糖单元添加到介导DNA修复途径的蛋白质的酶家族的创始成员。电离辐射诱导DNA链断裂，表明PARP-1抑制可能使肿瘤细胞对辐射敏感。实验设计：我们研究了PARP-1抑制与辐射在肺癌模型中的组合。结果：ABT-888可降低H460肺癌细胞的克隆形成存活率，并通过增强DNA链断裂标志物组蛋白γ-H2 AX的表达抑制DNA修复。细胞凋亡和自噬都是导致细胞死亡增加的机制。此外，ABT-888在小鼠模型中以良好耐受性增加肿瘤生长延迟。对于肿瘤体积增加5倍，ABT-888单独治疗的肿瘤生长延迟为1天，单独放射治疗为7天，联合治疗为13.5天。肿瘤切片的免疫组化染色显示，在联合治疗后，末端脱氧核糖核苷酸转移酶介导的缺口末端标记凋亡染色增加，Ki-67增殖染色减少。Matrigel分析显示ABT-888/放射联合治疗的体外内皮小管形成减少，肿瘤切片的von Willebrand因子染色显示体内血管形成减少，表明该策略也可能靶向肿瘤血管生成。我们的结论是，PARP-1抑制显示出作为增强肿瘤对辐射敏感性的有效手段的希望，未来的临床研究需要确定ABT-888作为放射增强剂的潜力。
Purpose: Poly (ADP-ribose) polymerase-1 (RARP-1) is the founding member of a family of enzymes that catalyze the addition of ADP-ribose units to proteins that mediate DNA repair pathways. Ionizing radiation induces DNA strand breaks, suggesting that PARP-1 inhibition may sensitize tumor cells to radiation.Experimental Design: We investigated the combination of PARP-1 inhibition with radiation in lung cancer models. ABT-888, a novel potent PARP-1 inhibitor, was used to explore the effects of PARP-1 inhibition on irradiated tumors and tumor vasculature.Results: ABT-888 reduced clonogenic survival in H460 lung cancer cells, and inhibited DNA repair as shown by enhanced expression of DNA strand break marker histone gamma-H2AX. Both apoptosis and autophagy contributed to the mechanism of increased cell death. Additionally, ABT-888 increased tumor growth delay at well-tolerated (loses in murine models. For a 5-fold increase in tumor volume, tumor growth delay was 1 day for ABT-888 alone, 7 days for radiation alone, and 13.5 days for combination treatment. Immunohistochemical staining of tumor sections revealed an increase in terminal deoxyribonucleotide transferase-mediated nick-end labeling apoptotic staining, and a decrease in Ki-67 proliferative staining after combination treatment. Matrigel assay showed a decrease in in vitro endothelial tubule formation with ABT-888/radiation combination treatment, and von Willebrand factor staining of tumor sections revealed decreased vessel formation in vivo, suggesting that this strategy may also target tumor angiogenesis.Conclusions: We conclude that PARP-1 inhibition shows promise as an effective means of enhancing tumor sensitivity to radiation, and future clinical studies are needed to determine the potential of ABT-888 as a radiation enhancer.