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The PI3K/mTOR Inhibitor Ompalisib Suppresses Nonhomologous End Joining and Sensitizes Cancer Cells to Radio- and Chemotherapy
Molecular Cancer Research ( IF 4.1 ) Pub Date : 2021-11-01 , DOI: 10.1158/1541-7786.mcr-21-0301
Jie Du 1, 2 , Fuqiang Chen 1 , Jiahua Yu 3 , Lijun Jiang 1 , Meijuan Zhou 1
Affiliation  

As the predominant pathway for the repair of DNA double-strand breaks (DSB), non-homologous end joining (NHEJ) attenuates the efficacy of cancer treatment which relies on the introduction of DSBs, such as radiotherapy and genotoxic drugs. Identifying novel NHEJ inhibitors is of great importance for improving the therapeutic efficiency of radio- or chemotherapy. Here we miniaturized our recently developed NHEJ detecting system into a 96-well plate-based format and interrogated an FDA approved drug library containing 1732 compounds. A collection of novel hits were considered to be potential DSB repair inhibitors at the noncytotoxic concentration. We identified omipalisib as an efficient sensitizer for DNA damage–induced cell death in vitro . Furthermore, in vitro analysis uncovered the repressive effect of omipalisib on the phosphorylation of DNA-dependent protein kinase catalytic subunit induced by ionizing radiation and doxorubicin, which led to the suppression of NHEJ pathway. Implications: In summary, our findings suggested the possibility for repurposing these candidates as radio- or chemosensitizers, which might extend their clinical application in cancer therapy. This article is featured in Highlights of This Issue, [p. 1793][1] [1]: /lookup/volpage/19/1793?iss=11

中文翻译:

PI3K/mTOR 抑制剂 Ompalisib 抑制非同源末端连接并使癌细胞对放疗和化疗敏感

作为修复 DNA 双链断裂 (DSB) 的主要途径,非同源末端连接 (NHEJ) 减弱了依赖于 DSB 引入的癌症治疗的功效,例如放射治疗和基因毒性药物。鉴定新的 NHEJ 抑制剂对于提高放疗或化疗的治疗效率非常重要。在这里,我们将我们最近开发的 NHEJ 检测系统小型化为基于 96 孔板的格式,并询问 FDA 批准的包含 1732 种化合物的药物库。一组新的命中被认为是非细胞毒性浓度的潜在 DSB 修复抑制剂。我们将 omipalisib 鉴定为体外 DNA 损伤诱导的细胞死亡的有效敏化剂。此外,体外分析揭示了 omipalisib 对电离辐射和阿霉素诱导的 DNA 依赖性蛋白激酶催化亚基磷酸化的抑制作用,从而导致 NHEJ 通路的抑制。启示:总之,我们的研究结果表明将这些候选物重新用作放射或化学增敏剂的可能性,这可能会扩展它们在癌症治疗中的临床应用。这篇文章被收录在本期的亮点中,[p. 1793][1][1]:/lookup/volpage/19/1793?iss=11 这篇文章被收录在本期的亮点中,[p. 1793][1][1]:/lookup/volpage/19/1793?iss=11 这篇文章被收录在本期的亮点中,[p. 1793][1][1]:/lookup/volpage/19/1793?iss=11
更新日期:2021-11-02
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