A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia
A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia
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DOI：
10.1016/j.radonc.2008.04.005
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发表时间：
2008-08-01
影响因子：
5.7
通讯作者：
Bristow, Robert G.
中科院分区：
文献类型：
--
作者：
Liu, Stanley K.;Coackley, Carla;Bristow, Robert G.
肿瘤细胞的化疗和放射反应可以通过遗传因素（例如，改变细胞周期停滞、DNA损伤修复或细胞死亡的那些）和微环境因素，如缺氧。聚（ADP-核糖）聚合酶（PARP）是一种快速识别并结合DNA断裂以促进DNA链断裂修复的核酶。临床前数据表明，PARP抑制剂（PARPi）可能会增强放疗和化疗的效果。然而，目前尚不清楚PARPi是否对缺氧细胞有效。因此，我们测试了新型PARPi（ABT-888）在缺氧条件下作为放射增敏剂的作用。使用人前列腺癌（DU-145，22 RV 1）和非小细胞肺癌（H1299）细胞系，我们观察到ABT-888抑制重组PARP活性和细胞内PARP活性（2.5 μ M处理后，所有3种细胞系均降低86%至92%）。ABT-888对缺氧细胞和好氧细胞均有毒性。当ABT-888与电离辐射（IR）联合使用时，在有氧条件下，克隆形成辐射存活率降低了40-50%。在急性缺氧条件下，ABT-888放射增敏恶性肿瘤细胞至与氧放射增敏性相似的水平。据我们所知，这是第一项证明抑制PARP活性可以使缺氧癌细胞增敏的研究，IR-PARPi的组合具有提高放射治疗率的潜力。(C)2008爱思唯尔爱尔兰有限公司保留所有权利。
The chemo- and radioresponse of tumor cells can be determined by genetic factors (e.g., those that modify cell cycle arrest, DNA damage repair or cell death) and microenvironmental factors, such as hypoxia. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that rapidly recognizes and binds to DNA breaks to facilitate DNA strand break repair. Preclinical data suggest that PARP inhibitors (PARPi) may potentiate the effects of radiotherapy and chemotherapy. However, it is unclear as to whether PARPi are effective against hypoxic cells. We therefore tested the role for a novel PARPi, ABT-888, as a radiosensitizing agent under hypoxic conditions. Using human prostate (DU-145, 22RV1) and non-small cell lung (H1299) cancer cell lines, we observed that ABT-888 inhibited both recombinant PARP activity and intracellular PARP activity (86% to 92% decrease in all 3 cells lines following 2.5 mu M treatment). ABT-888 was toxic to both oxic and hypoxic cells. When ABT-888 was combined with ionizing radiation (IR), clonogenic radiation survival was decreased by 40-50% under oxic conditions. Under acute hypoxia, ABT-888 radiosensitized malignant cells to a level similar to oxic radiosensitivity. To our knowledge, this is the first study to demonstrate that inhibition of PARP activity can sensitize hypoxic cancer cells and the combination of IR-PARPi has the potential to improve the therapeutic ratio of radiotherapy. (C) 2008 Elsevier Ireland Ltd. All rights reserved.