1. BIBR1532, a Selective Telomerase Inhibitor, Enhances Radiosensitivity of Non-Small Cell Lung Cancer Through Increasing Telomere Dysfunction and ATM/CHK1 Inhibition
- Author
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Xiaoying Wei, Ping Wang, Dong Qian, Zhiyong Yuan, Xiaofeng Ding, Jingjing Cheng, Ximei Zhang, and Qingsong Pang
- Subjects
Radiation-Sensitizing Agents ,Cancer Research ,Telomerase ,Radiosensitizer ,Lung Neoplasms ,DNA Repair ,Cell ,Mice, Nude ,Ataxia Telangiectasia Mutated Proteins ,Naphthalenes ,Radiation Tolerance ,Sincalide ,030218 nuclear medicine & medical imaging ,Mice ,03 medical and health sciences ,Enzyme Reactivators ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Animals ,Humans ,Medicine ,Aminobenzoates ,Radiology, Nuclear Medicine and imaging ,Radiosensitivity ,CHEK1 ,Enzyme Inhibitors ,Phosphorylation ,Mitotic catastrophe ,Cellular Senescence ,Cell Proliferation ,Radiation ,Cell Death ,Dose-Response Relationship, Drug ,business.industry ,Cell growth ,Telomere Homeostasis ,Telomere ,Xenograft Model Antitumor Assays ,Enzyme Activation ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,business ,DNA Damage - Abstract
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 β-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.
- Published
- 2019