BIBR1532, a Selective Telomerase Inhibitor, Enhances Radiosensitivity of Non-Small Cell Lung Cancer Through Increasing Telomere Dysfunction and ATM/CHK1 Inhibition
BIBR1532, a Selective Telomerase Inhibitor, Enhances Radiosensitivity of Non-Small Cell Lung Cancer Through Increasing Telomere Dysfunction and ATM/CHK1 Inhibition
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BIBR1532 是一种选择性端粒酶抑制剂，通过增加端粒功能障碍和 ATM/CHK1 抑制来增强非小细胞肺癌的放射敏感性
DOI：
10.1016/j.ijrobp.2019.08.009
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发表时间：
2019-11-15
影响因子：
7
通讯作者：
Qian, Dong
中科院分区：
文献类型：
--
作者：
Ding, Xiaofeng;Cheng, Jingjing;Qian, Dong
目的：端粒酶在非小细胞肺癌（NSCLC）中被重新激活，它通过保护受损的端粒和增强DNA损伤修复来增强细胞对辐射的抵抗力。我们研究了高选择性端粒酶抑制剂BIBR1532在非小细胞肺癌中的放射增敏作用及其相应机制。方法与材料：采用CCK-8法、实时荧光定量聚合酶链反应法和免疫荧光法检测细胞增殖、端粒酶活性和端粒功能障碍诱导的病灶。通过克隆生存和异种移植肿瘤实验分析BIBR1532对NSCLC细胞对辐射反应的影响。采用western blotting、流式细胞术和衰老相关β -半乳糖苷酶染色法检测BIBR1532或电离辐射（IR）或两者诱导的细胞死亡和细胞衰老。结果：在相对高浓度的情况下，我们观察到BIBR1532在非小细胞肺癌细胞中的剂量依赖性直接细胞毒性。低浓度BIBR1532对NSCLC细胞没有毒性；然而，它们通过增强IR诱导的细胞凋亡、衰老和有丝分裂突变，在体外显著提高了IR的治疗效果。此外，在小鼠异种移植模型中，BIBR1532治疗与IR在无毒剂量水平下协同作用，促进了IR的抗肿瘤功效，而对血液和内脏器官没有毒性。在机制上，低浓度BIBR1532有效抑制端粒酶活性，增加ir诱导的端粒功能障碍，导致染色体稳定性破坏，抑制ATM/CHK1（失调性毛细血管扩张-突变/检查点激酶1）通路，从而损害DNA损伤修复。结论：我们的研究结果表明，无毒剂量水平的BIBR1532对端粒酶功能的干扰有效地增强了NSCLC细胞的放射敏感性。这一发现为临床评估BIBR1532作为放射增敏剂提供了依据。(C) 2019作者。Elsevier Inc.出版。
Purpose: Telomerase is reactivated in non-small cell lung cancer (NSCLC), and it increases cell resistance to irradiation through protecting damaged telomeres and enhancing DNA damage repair. We investigated the radiosensitizing effect of BIBR1532, a highly selective telomerase inhibitor, and its corresponding mechanism in NSCLC.Methods and Materials: Cell proliferation, telomerase activity, and telomere dysfunction-induced foci were measured with CCK-8 assay, real-time fluorescent quantitative polymerase chain reaction, and immunofluorescence. The effect of BIBR1532 on the response of NSCLC cells to radiation was analyzed using clonogenic survival and xenograft tumor assays. Cell death and cell senescence induced by BIBR1532 or ionizing radiation (IR), or both, were detected with western blotting, flow cytometry, and senescence-association beta-galactosidase staining assay.Results: We observed dose-dependent direct cytotoxicity of BIBR1532 at relatively high concentrations in NSCLC cells. Low concentrations of BIBR1532 did not appear toxic to NSCLC cells; however, they substantially increased the therapeutic efficacy of IR in vitro by enhancing IR-induced apoptosis, senescence, and mitotic catastrophe. Moreover, in a mouse xenograft model, BIBR1532 treatment synergized with IR at nontoxic dose levels promoted the antitumor efficacy of IR without toxicity to hematologic and internal organs. Mechanistically, lower concentrations of BIBR1532 effectively inhibited telomerase activity and increased IR-induced telomere dysfunction, resulting in disruption of chromosomal stability and inhibition of the ATM/CHK1 (ataxia-telangiectasia-mutated/Checkpoint kinase 1) pathway, which impaired DNA damage repair.Conclusions: Our findings demonstrate that disturbances in telomerase function by nontoxic dose levels of BIBR1532 effectively enhance the radiosensitivity of NSCLC cells. This finding provides a rationale for the clinical assessment of BIBR1532 as a radiosensitizer. (C) 2019 The Authors. Published by Elsevier Inc.