Li Xiaoli, Liu Dan, Liu Xin, Jiang Weiwei, Zhou Weiying, Yan Wei, Cen Yanyan, Li Bin, Cao Guanqun, Ding Guofu, Pang Xueli, Sun Jianguo, Zheng Jiang, Zhou Hong
Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Gaotanyan Street 30, Shapingba District, Chongqing, 400038, People's Republic of China.
Tumour Biol. 2012 Oct;33(5):1607-18. doi: 10.1007/s13277-012-0416-1. Epub 2012 Jun 28.
Radiotherapy is a standard treatment for glioma patient with or without surgery; radiosensitizer can increase tumor sensitivity for radiotherapy. Herein, a synthetic oligodeoxynucleotide containing unmethylated CpG dinucleotides (CpG ODN107) as a radiosensitizer was investigated in vitro and in vivo, and the possible mechanisms were studied in vitro. In the present experiments, the human glioma U87 cell line used herein was resistant to 5 Gy of β-ray irradiation. The results showed that 10 μg/ml of CpG ODN107 in combination with irradiation significantly inhibited cell proliferation both in MTT assay and colony formation experiments. Tumor growth was inhibited by CpG ODN107 in combination with local irradiation but not by local irradiation or CpG ODN107 alone in human glioma xenograft model in nude mice. The inhibition ratio of tumor growth produced by CpG ODN107 (1.7, 5, and 15 mg/kg) in combination with irradiation was 27.3, 67.0, and 65.5 %, respectively. Further molecular mechanisms were studied in vitro. The results showed that the expressions of iNOS, NO, TLR9 mRNA, and NF-κB p50/p65 increased in the cells treated with CpG ODN107 in combination with irradiation. CpG ODN107 in combination with irradiation did not induce apoptosis but induced cell cycle arrest at G(1) phase. The said results demonstrated that CpG ODN107 possessed a radiosensitizing effect via TLR9-mediated NF-κB activation and NO production in the tumor cells, leading to cell cycle arrest. Therefore, CpG ODN107 is a potential candidate as radiosensitizer for human glioma.
放射治疗是胶质瘤患者无论是否接受手术的标准治疗方法；放射增敏剂可提高肿瘤对放射治疗的敏感性。在此，研究了一种含未甲基化CpG二核苷酸的合成寡脱氧核苷酸（CpG ODN107）作为放射增敏剂在体外和体内的作用，并在体外研究了其可能的机制。在本实验中，所用的人胶质瘤U87细胞系对5 Gy的β射线照射具有抗性。结果表明，在MTT试验和集落形成实验中，10 μg/ml的CpG ODN107与照射联合使用可显著抑制细胞增殖。在裸鼠人胶质瘤异种移植模型中，CpG ODN107与局部照射联合使用可抑制肿瘤生长，但单独局部照射或单独使用CpG ODN107则无此作用。CpG ODN107（1.7、5和15 mg/kg）与照射联合使用对肿瘤生长的抑制率分别为27.3%、67.0%和65.5%。进一步在体外研究了分子机制。结果表明，CpG ODN107与照射联合处理的细胞中，诱导型一氧化氮合酶（iNOS）、一氧化氮（NO）、Toll样受体9（TLR9）mRNA和核因子κB（NF-κB）p50/p65的表达增加。CpG ODN107与照射联合使用未诱导细胞凋亡，但诱导细胞周期停滞于G(1)期。上述结果表明，CpG ODN107通过TLR9介导的NF-κB激活和肿瘤细胞中NO的产生而具有放射增敏作用，导致细胞周期停滞。因此，CpG ODN107是人类胶质瘤放射增敏剂的潜在候选物。
