Radiosensitization by the PARP inhibitor olaparib in BRCA1-proficient and deficient high-grade serous ovarian carcinomas
Radiosensitization by the PARP inhibitor olaparib in BRCA1-proficient and deficient high-grade serous ovarian carcinomas
复制标题
DOI：
10.1016/j.ygyno.2018.07.002
复制
发表时间：
2018-09-01
影响因子：
4.7
通讯作者：
Koumenis, Constantinos
中科院分区：
文献类型：
--
作者：
Bi, Yue;Verginadis, Ioannis I.;Koumenis, Constantinos
目标。大约15-25%的高级别浆液性卵巢癌（HGSOC）携带BRCA1/2突变。抑制聚（adp -核糖）聚合酶（PARP）对BRCA1/2突变的细胞和肿瘤具有合成致死性。我们的目的是研究PARP抑制剂奥拉帕尼在不同BRCA1状态的HGSOC中的放射增敏作用。通过克隆生存和肿瘤生长试验，检测奥拉帕尼对brca1精通和缺乏的HGSOC的放射增敏作用。测定奥拉帕尼和辐射对DNA损伤、PARP活性和细胞凋亡的影响。brca1缺失的HGSOC细胞对RT更敏感，并且与brca1精通的细胞相比，表现出更高水平的奥拉帕尼介导的放射增敏。此外，当与RT联合使用时，奥拉帕尼抑制DNA损伤修复和PARP1活性，增加凋亡，降低HGSOC异种移植物的生长，提高总体宿主存活率。与brca1富集的肿瘤相比，奥拉帕尼联合RT治疗对brca1缺失肿瘤小鼠的生长抑制作用更为明显。这些结果为使用奥拉帕尼作为HGSOC的有效放射增敏剂改善治疗方式提供了临床前理论依据，特别是在brcal缺乏的肿瘤中。(C) 2018年Elsevier Inc.出版
Objective. Approximately 15-25% of high-grade serous ovarian carcinomas (HGSOC) harbor BRCA1/2 mutations. Inhibition of Poly (ADP-ribose) polymerase (PARP) is synthetically lethal to cells and tumors with BRCA1/2 mutation. Our goal was to investigate the radiosensitizing effects of PARP inhibitor olaparib in HGSOC with different BRCA1 status.Methods. The radiosensitizing effects of olaparib were tested on BRCA1-proficient and deficient HGSOC by clonogenic survival and tumor growth assays. The effects of olaparib and radiation on DNA damage, PARP activity, and apoptosis were determined.Results. BRCA1-deficient HGSOC cells were more sensitive to RT alone and exhibited significantly higher levels of olaparib-mediated radiosensitization compared to BRCA1-proficient cells. Furthermore, when combined with RT, olaparib inhibited DNA damage repair and PARP1 activity, increased apoptosis, decreased growth of HGSOC xeno-grafts and increased overall host survival. The growth-inhibitory effects of the combined olaparib and RT treatment were more pronounced in mice bearing BRCAl-deficient tumors compared to BRCA1-proficient tumors.Conclusions. These results provide a preclinical rationale for improved treatment modalities using olaparib as an effective radiosensitizer in HGSOC, particularly in tumors with BRCAl-deficiencies. (C) 2018 Published by Elsevier Inc.