Xiaofeng Ding1, Jingjing Cheng2, Qingsong Pang1, Xiaoying Wei3, Ximei Zhang1, Ping Wang1, Zhiyong Yuan4, Dong Qian5. 1. Department of Radiation Oncology and Cyberknife Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China. 2. Department of Radiation Oncology and Cyberknife Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Radiation Oncology, First Affiliated Hospital of USTC(University of Science and Technology of China), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. 3. Department of Radiation Oncology and Cyberknife Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China. 4. Department of Radiation Oncology and Cyberknife Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China. Electronic address: zhiyong0524@163.com. 5. Department of Radiation Oncology and Cyberknife Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Radiation Oncology, First Affiliated Hospital of USTC(University of Science and Technology of China), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. Electronic address: qiankeyu1983@163.com.
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.
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.
Authors: Shengnan Yu; Shiyou Wei; Milan Savani; Xiang Lin; Kuang Du; Ilgen Mender; Silvia Siteni; Themistoklis Vasilopoulos; Zachary J Reitman; Yin Ku; Di Wu; Hao Liu; Meng Tian; Yaohui Chen; Marilyne Labrie; Casey M Charbonneau; Eric Sugarman; Michelle Bowie; Seethalakshmi Hariharan; Matthew Waitkus; Wen Jiang; Roger E McLendon; Edward Pan; Mustafa Khasraw; Kyle M Walsh; Yiling Lu; Meenhard Herlyn; Gordon Mills; Utz Herbig; Zhi Wei; Stephen T Keir; Keith Flaherty; Lunxu Liu; Kongming Wu; Jerry W Shay; Kalil Abdullah; Gao Zhang; David M Ashley Journal: Clin Cancer Res Date: 2021-09-30 Impact factor: 13.801
Authors: Gennaro Altamura; Barbara Degli Uberti; Giorgio Galiero; Giovanna De Luca; Karen Power; Luca Licenziato; Paola Maiolino; Giuseppe Borzacchiello Journal: Front Vet Sci Date: 2021-01-20
Authors: Haytham O Tawfik; Anwar A El-Hamaky; Eman A El-Bastawissy; Kirill A Shcherbakov; Alexander V Veselovsky; Yulia A Gladilina; Dmitry D Zhdanov; Mervat H El-Hamamsy Journal: Pharmaceuticals (Basel) Date: 2022-04-14