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二甲基氨基瑞香素抑制核因子-κB通过阻断DNA双链断裂修复使非小细胞肺癌对放疗增敏。

NF-κB inhibition by dimethylaminoparthenolide radiosensitizes non-small-cell lung carcinoma by blocking DNA double-strand break repair.

作者信息

Deraska Peter V, O'Leary Colin, Reavis Hunter D, Labe Shelby, Dinh Tru-Khang, Lazaro Jean-Bernard, Sweeney Christopher, D'Andrea Alan D, Kozono David

机构信息

1Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA USA.

2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA USA.

出版信息

Cell Death Discov. 2018 Feb 7;4:10. doi: 10.1038/s41420-017-0008-3. eCollection 2018 Dec.

DOI:10.1038/s41420-017-0008-3
PMID:29531807
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5841323/
Abstract

Despite optimal chemotherapy, radiotherapy (RT), and/or surgery, non-small-cell lung carcinoma (NSCLC) remains the leading cause of cancer-related death in the US and worldwide. Thoracic RT, a mainstay in the treatment of locally advanced NSCLC, is often restricted in efficacy by a therapeutic index limited by sensitivity of tissues surrounding the malignancy. Therefore, radiosensitizers that can improve the therapeutic index are a vital unmet need. Inhibition of the NF-κB pathway is a proposed mechanism of radiosensitization. Here we demonstrate that inhibition of the canonical NF-κB pathway by dimethylaminoparthenolide (DMAPT) radiosensitizes NSCLC by blocking DNA double-strand break (DSB) repair. NF-κB inhibition results in significant impairment of both homologous recombination (HR) and non-homologous end joining (NHEJ), as well as reductions in ionizing radiation (IR)-induced DNA repair biomarkers. NF-κB inhibition by DMAPT shows preclinical potential for further investigation as a NSCLC radiosensitizer.

摘要

尽管采用了最佳的化疗、放疗（RT）和/或手术，但非小细胞肺癌（NSCLC）仍然是美国和全球癌症相关死亡的主要原因。胸部放疗是局部晚期NSCLC治疗的主要手段，但其疗效常常受到肿瘤周围组织敏感性所限的治疗指数的限制。因此，能够提高治疗指数的放射增敏剂是一项至关重要的未满足需求。抑制NF-κB信号通路是一种放射增敏的机制。在此我们证明，二甲基氨基半日花醇酯（DMAPT）对经典NF-κB信号通路的抑制作用通过阻断DNA双链断裂（DSB）修复使NSCLC对放疗更加敏感。抑制NF-κB会导致同源重组（HR）和非同源末端连接（NHEJ）均受到显著损害，同时也会使电离辐射（IR）诱导的DNA修复生物标志物减少。DMAPT对NF-κB的抑制作用显示出作为NSCLC放射增敏剂进行进一步研究的临床前潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee7f/5841323/6b1bb4ca892c/41420_2017_8_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee7f/5841323/86ed0c537572/41420_2017_8_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee7f/5841323/bde0b607b2ec/41420_2017_8_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee7f/5841323/17ca7a25b609/41420_2017_8_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee7f/5841323/6b1bb4ca892c/41420_2017_8_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee7f/5841323/86ed0c537572/41420_2017_8_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee7f/5841323/bde0b607b2ec/41420_2017_8_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee7f/5841323/17ca7a25b609/41420_2017_8_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee7f/5841323/6b1bb4ca892c/41420_2017_8_Fig4_HTML.jpg

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