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CpG ODN107 potentiates radiosensitivity of human glioma cells via TLR9-mediated NF-κB activation and NO production

  • Research Article
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Tumor Biology

Abstract

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 G1 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.

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Abbreviations

CpG ODN:

Oligodeoxynucleotides containing unmethylated CG dinucleotides

LPS:

Lipopolysacchride

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

NO:

Nitric oxide

iNOS:

Inducible nitric oxide synthase

NF-κB:

Nuclear factor-κB

IR:

Irradiation

TLR:

Toll-like receptor

IC10 :

Inhibitor concentration at which 10 % enzyme inhibition occurs

TGD:

Tumor growth delay

TVQT:

Tumor volumes quadrupling time

SF:

Surviving fraction.

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Acknowledgments

Financial support was provided from a major scientific and technological special project for “Significant New Drugs Creation” of China (2009ZX09103-051). Thanks are also due to senior technician Hong Xiao, Technician Xi Wang, and Zhan Jiang in Department of Oncology of Southwest Hospital for technical assistance.

Conflicts of interest

None.

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Authors and Affiliations

  1. Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Gaotanyan Street 30, Shapingba District, Chongqing, 400038, People’s Republic of China

    Xiaoli Li, Dan Liu, Weiwei Jiang, Weiying Zhou, Wei Yan, Yanyan Cen, Bin Li, Guofu Ding & Hong Zhou

  2. Medical Research Center, Southwest Hospital, The Third Military Medical University, Gaotanyan Street 30, Shapingba District, Chongqing, 400038, People’s Republic of China

    Xin Liu & Jiang Zheng

  3. Company 15th, Students of Brigade, The Third Military Medical University, Chongqing, 400038, China

    Guanqun Cao

  4. Department of Oncology, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China

    Xueli Pang

  5. Department of Oncology, Xinqiao Hospital, The Third Military Medical University, Chongqing, 400038, China

    Jianguo Sun

Authors
  1. Xiaoli Li
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  2. Dan Liu
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  3. Xin Liu
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  8. Bin Li
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  13. Jiang Zheng
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  14. Hong Zhou
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Corresponding authors

Correspondence to Jiang Zheng or Hong Zhou.

Additional information

Xiaoli Li and Dan Liu contributed equally to this work.

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Li, X., Liu, D., Liu, X. et al. CpG ODN107 potentiates radiosensitivity of human glioma cells via TLR9-mediated NF-κB activation and NO production. Tumor Biol. 33, 1607–1618 (2012). https://doi.org/10.1007/s13277-012-0416-1

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  • DOI: https://doi.org/10.1007/s13277-012-0416-1

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