The PARP-1 inhibitor Olaparib suppresses BRCA1 protein levels, increases apoptosis and causes radiation hypersensitivity in BRCA1(+/-) lymphoblastoid cells.
The PARP-1 inhibitor Olaparib suppresses BRCA1 protein levels, increases apoptosis and causes radiation hypersensitivity in BRCA1(+/-) lymphoblastoid cells.
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DOI：
10.7150/jca.21338
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发表时间：
2017
影响因子：
3.9
通讯作者：
Parris CN
中科院分区：
文献类型：
--
作者：
Bourton EC;Ahorner PA;Plowman PN;Zahir SA;Al-Ali H;Parris CN
在癌症治疗中使用PolyADPribose聚合酶抑制剂提供了一个独特的机会，可以在不影响正常组织的情况下针对癌细胞中的DNA修复过程进行靶向。PARP-1酶修复DNA单链断裂(SSB)。因此，在BRCA1阴性的癌症中抑制PARP-1会导致细胞毒性DNA双链断裂(DSB)的形成，从而导致合成致命性。在包括乳腺癌、卵巢癌、胰腺癌和前列腺癌在内的多种BRCA1相关肿瘤的治疗中，PARP1抑制剂的使用势头正在增强。我们以前的工作表明，PARP-1抑制剂奥拉帕利导致伽玛射线照射后BRCA1+/-细胞的超敏反应，这是由于细胞中持续的DNA链断裂，由DNA损伤生物标记物γ-H2AX测量。因此，癌症放疗和PARP1抑制的双重治疗可能会导致癌症患者正常组织毒性增加。在这项研究中，我们将两个正常的淋巴母细胞系和三个杂合子的BRCA1淋巴母细胞系暴露于PARP-1抑制剂奥拉帕利和伽玛射线，并在治疗后检测BRCA1的蛋白表达和细胞凋亡水平。在有或没有5μM奥拉帕利存在的情况下，对2Gy射线照射的细胞进行BRCA1蛋白焦点分析。分别于照射后0.5、3、5、24小时，用免疫荧光和流式细胞术对未处理细胞的病灶进行检测。正常细胞和BRCA1+/-细胞经奥拉帕利和伽玛射线照射后，BRCA1蛋白表达显著改变，杂合子细胞中BRCA1蛋白表达显著降低，同时这些细胞的凋亡水平增加。总而言之，在BRCA1相关癌症的治疗中，联合使用PARP1抑制剂和放射治疗具有临床意义，然而，这项研究和我们之前的出版物强调了在这些情况下副作用增加的潜在问题。
The use of polyADPribose polymerase inhibitors in cancer treatment provides a unique opportunity to target DNA repair processes in cancer cells while leaving normal tissue intact. The PARP-1 enzyme repairs DNA single strand breaks (SSB). Therefore PARP-1 inhibition in BRCA1 negative cancers results in the formation of cytotoxic DNA double strand breaks (DSB) causing synthetic lethality. The use of PARP1 inhibitors is gaining momentum in the treatment of a variety of tumours with BRCA1 involvement including breast, ovarian, pancreatic and prostate cancer. Our previous work showed that the PARP-1 inhibitor Olaparib causes both hypersensitivity of BRCA1+/- cells following exposure to gamma radiation due to the persistence of DNA strand breaks in cells, measured by the DNA damage biomarker γ-H2AX. Therefore dual treatment of cancers with radiotherapy and PARP1 inhibition may lead to cases of increased normal tissue toxicity in cancer patients. In this study we exposed two normal lymphoblastoid cell lines and three heterozygous BRCA1 lymphoblastoid cell lines to the PARP-1 inhibitor Olaparib and gamma radiation and after measured BRCA1 protein expression and apoptosis levels following treatment. BRCA1 protein foci analysis was performed on cells exposed to 2 Gy radiation in the presence or absence of 5 μM Olaparib. Using immunofluorescence and imaging flow cytometry, foci were measured in untreated cells and at 0.5, 3, 5 and 24 hours post-irradiation. Exposing normal and BRCA1+/- cells to Olaparib followed by gamma radiation results in a dramatic change in BRCA1 protein foci expression, with a significant reduction in BRCA1 protein expression observed in the heterozygote cells, together with an increase in apoptosis levels in these cells. In conclusion, combining PARP1 inhibitors with radiotherapy in treating of BRCA1-related cancers has clinical relevance, however this study and our previous publications serve to highlight the potential problems of increased side effects in these scenarios.
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影响因子：
6.2
作者：
Delaney, G;Jacob, S;Barton, M
通讯作者：
Barton, M
DOI：
10.4161/cc.7.18.6679
发表时间：
2008-09-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Mao Z;Bozzella M;Seluanov A;Gorbunova V
通讯作者：
Gorbunova V
影响因子：
6.4
作者：
Buchholz, TA;Wu, XF;Brock, WA
通讯作者：
Brock, WA
BRCA1和BRCA2在双链断裂修复中的不同功能。
DOI：
10.1186/bcr417
发表时间：
2002
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Liu Y;West SC
通讯作者：
West SC
DOI：
10.1186/s13058-016-0739-8
发表时间：
2016-08-17
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Chehade R;Pettapiece-Phillips R;Salmena L;Kotlyar M;Jurisica I;Narod SA;Akbari MR;Kotsopoulos J
通讯作者：
Kotsopoulos J