SpringerLink
Log in

Antitumor and radiosensitization effect of 12C6+ heavy-ion irradiation mediated by radiation-inducible gene therapy

  • Published:
Nuclear Science and Techniques Aims and scope Submit manuscript

Abstract

Radio genetic therapy which combines gene therapy with radiotherapy has shown promising results in cancer treatment. In this study, an oncolytic adenovirus-based gene therapy system regulated by radiation was constructed to improve the cancer curative effect. This gene therapy system incorporated the radiation-inducible early growth response gene (Egr-1) promoter and the anticancer gene tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). To confirm the antitumor effect of Ad-ET combined with \(^{12}\hbox {C}^{6+}\) ion irradiation, the survival and apoptosis fraction of tumor cells HT1080 and normal cells MRC-5 in combination treatment were detected by CCK-8 assay and FACS analysis. Then the expression levels of TRAIL gene and protein were tested by real-time PCR and western blotting. The results show that \(^{12}\hbox {C}^{6+}\) ion irradiation could induce cell growth inhibition and apoptosis by activating the TRAIL gene expression in tumor cells, while exhibiting no obvious toxicity to the normal lung cell line MRC-5. The results also demonstrate that use of an oncolytic adenovirus-based radiation-inducible gene therapy system together with \(^{12}\hbox {C}^{6+}\) ion irradiation could cause synergistic antitumor effect specifically in tumor cells but not in normal cells. The results indicate that the novel radio genetic therapy could potentiate radiation treatment by improving the safety and efficiency of monotherapy, and provide theoretical support for clinical application of combination treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. I.M. Verma, N. Somia, Gene therapy-promises, problems and prospects. Nature 389, 239–242 (1997). doi:10.1038/38410

    Article  Google Scholar 

  2. M.L. Edelstein, M.R. Abedi, J. Wixon et al., Gene therapy clinical trials worldwide 1989–2004-an overview. J. Gene. Med. 6, 597–602 (2004). doi:10.1002/jgm.619

    Article  Google Scholar 

  3. R.D. Alvarez, J. Gomez-Navarro, M. Wang et al., Adenoviral-mediated suicide gene therapy for ovarian cancer. Mol. Ther. 2, 524–530 (2000). doi:10.1006/mthe.2000.0194

    Article  Google Scholar 

  4. K. Garber, China approves world’s first oncolytic virus therapy for cancer treatment. J. Natl. Cancer. Inst. 98, 298–300 (2006). doi:10.1093/jnci/djj111

    Article  Google Scholar 

  5. H. LeBlanc, A. Ashkenazi, Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ, 10, 66–75 (2003). doi:10.1038/sj.cdd.4401187

    Article  Google Scholar 

  6. A. Ashkenazi, R. Pal, S. Fong et al., Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest. 104, 155–162 (1999). doi:10.1172/JCI6926

    Article  Google Scholar 

  7. G. Pan, G. Ni, Y.F. Wei et al., An antagonist decoy recep-tor and a death domain-containing receptor for TRAIL. Science 277, 815–818 (1997). doi:10.1126/science.277.5327.815

    Article  Google Scholar 

  8. T. Hori, T. Kondo, M. Kanamori et al., Ionizing radiation enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through up-regulations of death receptor 4 (DR4) and death receptor 5 (DR5) in human osteosarcoma cells. J. Orthop. Res. 28, 739–745 (2009). doi:10.1002/jor.21056

    Google Scholar 

  9. A.M. Chinnaiyan, U. Prasad, S. Shankar et al., Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy. Proc. Natl. Acad. Sci. 97, 1754–1759 (2000). doi:10.1073/pnas.030545097

    Article  Google Scholar 

  10. W. Liu, E. Bodle, J. Chen et al., Tumor necrosis factor-related apoptosis-inducing ligand and chemotherapy cooperate to induce apoptosis in mesothelioma cell lines. Am. J. Respir. Cell Mol. 25, 111–118 (2001). doi:10.1165/ajrnmeterb.25.1.4472

    Article  Google Scholar 

  11. P. Todd, Heavy-ion irradiation of cultured human cells. Radiat. Res. Suppl. 7, 196–207 (1967). doi:10.2307/3583713

    Article  Google Scholar 

  12. T. Kanai, M. Endo, S. Minohara et al., Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy. Int. J. Radiat. Oncol. 44, 201–210 (1999). doi:10.1016/S0360-3016(98)00544-6

    Article  Google Scholar 

  13. H. Tsujii, J. Mizoe, T. Kamada et al., Clinical results of carbon ion radiotherapy at NIRS. J. Radiat. Res. 48, A1–13 (2007). doi:10.1269/jrr.48.A1

    Article  Google Scholar 

  14. H. Tsujii, J. Mizoe, T. Kamada et al., Overview of clinical experiences on carbon ion radiotherapy at NIRS. Radiother. Oncol. 73, S41–S49 (2004). doi:10.1016/S0167-8140(04)80012-4

    Article  Google Scholar 

  15. J.R. Castro, D.H. Char, P.L. Petti et al., 15 years experience with helium ion radiotherapy for uveal melanoma. Int. J. Radiat. Oncol. 39, 989–996 (1997). doi:10.1016/S0360-3016(97)00494-X

    Article  Google Scholar 

  16. A. Gashler, V.P. Sukhatme, Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors. Prog. Nucleic Acid Res. Mol. Biol. 50, 191–224 (1995). doi:10.1016/S0079-6603(08)60815-6

    Article  Google Scholar 

  17. R. Datta, E. Rubin, V. Sukhatme et al., Ionizing radiation activates transcription of the EGR1 gene via CArG elements. Proc. Natl. Acad. Sci. 89, 10149–10153 (1992)

    Article  Google Scholar 

  18. R.G. Meyer, J.H. Küpper, R. Kandolf et al., Early growth response-1 gene (Egr-1) promoter induction by ionizing radiation in U87 malignant glioma cells in vitro. Eur. J. Biochem. 269, 337–346 (2002). doi:10.1046/j.0014-2956.2001.02658.x

    Article  Google Scholar 

  19. T. Joki, M. Nakamura, T. Ohno, Activation of the radiosensitive EGR-1 promoter induces expression of the herpes simplex virus thymidine kinase gene and sensitivity of human glioma cells to ganciclovir. Human Gene Ther. 6, 1507–1513. doi:10.1089/hum.1995.6.12-1507

  20. H.B. Wang, X. Song, H. Zhang, Potentiation of tumor radiotherapy by a radiation-inducible oncolytic and oncoapoptotic adenovirus in cervical cancer xenografts. Int. J. Cancer 130, 443–453 (2012). doi:10.1002/ijc.26013

    Article  Google Scholar 

  21. C.A. Heid, J. Stevens, K.J. Livak et al., Real time quantitative PCR. Genome Res. 6, 986–994 (1996). doi:10.1101/gr.6.10.986

    Article  Google Scholar 

  22. Y.C. Wu, G. Song, R.F. Cao et al., Development of accurate/advanced radiotherapy treatment planning and quality assurance system (ARTS). Chin. Phys. C 32, 177–182 (2008)

    Article  Google Scholar 

  23. S. Tao, Y. Wu, Y. Chen et al., Repeated positioning in accurate radiotherapy based on virtual net technique and contrary reconstruction scheme. Comput. Med. Imaging Graph. 30, 273–278 (2006). doi:10.1016/j.compmedimag.2006.05.006

    Article  Google Scholar 

  24. S. Tao, A. Wu, Y. Wu et al., Patient set-up in radiotherapy with video-based positioning system. Clin. Oncol. 18, 363–366 (2006). doi:10.1016/j.clon.2005.11.018

    Article  Google Scholar 

  25. R.F. Cao, Y.C. Wu, X. Pei et al., Multi-objective optimization of inverse planning for accurate radiotherapy. Chin. Phys. C 35, 313–317 (2011). doi:10.1088/1674-1137/35/3/019

    Article  Google Scholar 

  26. Y.C. Wu, Development of reliability and probabilistic safety assessment program RiskA. Ann. Nucl. Energy 83, 316–321 (2015). doi:10.1016/j.anucene.2015.03.020

    Article  Google Scholar 

  27. J. Song, G. Sun, Z. Chen et al., Benchmarking of CAD-based SuperMC with ITER Benchmark Model. Fusion Eng. Des. 89, 2499–2503 (2014). doi:10.1016/j.fusengdes.2014.05.003

    Article  Google Scholar 

  28. L. Hu, Y. Wu, Probabilistic safety assessment of the dual-cooled waste transmutation blanket for the FDS-I. Fusion Eng. Des. 81, 1403–1407 (2006). doi:10.1016/j.fusengdes.2005.08.091

    Article  Google Scholar 

  29. H. Zheng, G. Sun, G. Li, et al., Photon dose calculation method based on Monte Carlo finite-size pencil beam model in accurate radiotherapy. Commun. Comput. Phys. 14, 1415–1422 (2013)

    Google Scholar 

  30. Y. Wu, G. Li, S. Tao et al., Research and development of an accurate/advanced radiation therapy system (ARTS). Chin. J. Med. Phys. 22, 683–690 (2006). doi:10.3969/j.issn.1005-202X.2005.06.001

    Google Scholar 

  31. W.Y. Li, R.F. Cao, X. Pei et al., Radiotherapy reliability analysis based on PSA method. Nucl. Sci. Tech. 25, 060501 (2014). doi:10.13538/j.1001-8042/nst.25.060501

    Google Scholar 

  32. K. Zhao, M.Y. Cheng, P.C. Long et al., A hybrid voxel sampling method for constructing Rad-HUMAN phantom. Nucl. Sci. Tech. 25, 020503 (2014). doi:10.13538/j.1001-8042/nst.25.020503

    Google Scholar 

  33. J. Wang, X. Pei, R.F. Cao et al., A multiphase direct aperture optimization for inverse planning in radiotherapy. Nucl. Sci. Tech. 26, 010502 (2015). doi:10.13538/j.1001-8042/nst.26.010502

    Google Scholar 

  34. R.R. Weichselbaum, D.E. Hallahan, M.A. Beckett et al., Gene Therapy targeted by radiation preferentially radiosensitized tumor cells. Cancer Res. 54, 4266–4269 (1994)

    Google Scholar 

  35. V.K. Gupta, J.O. Park, N.T. Jackowiak et al., Combined gene therapy and ionizing radiation is a novel approach to treat human esophageal adenocarcinoma. Ann. Surg. Oncol. 9, 500–504 (2002). doi:10.1007/BF02557275

    Article  Google Scholar 

  36. R.R. Weichselbaum, D.E. Hallahan, V.P. Sukhatme et al., Gene therapy targeted by ionizing radiation. Int. J. Radiat. Oncol. 24, 565–567 (1992). doi:10.1016/0360-3016(92)91075-X

    Article  Google Scholar 

  37. E. Wissink, I. Verbrugge, S. Vink et al., TRAIL enhances efficacy of radiotherapy in a p53 mutant, Bcl-2 overexpressing lymphoid malignancy. Radiother. Oncol. 80, 214–222 (2006). doi:10.1016/j.radonc.2006.07.030

    Article  Google Scholar 

  38. D. Lawrence, Z. Shahrokh, S. Marsters et al., Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat. Med. 7, 383–385 (2001). doi:10.1038/86397

    Article  Google Scholar 

  39. C. Belka, B. Schmid, P. Marini et al., Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL. Oncogene 20, 2190–2196 (2001)

    Article  Google Scholar 

Download references

Acknowledgments

We thank other members of the FDS team for their assistance in this work. We thank Professors ZHOU Guang-Ming and HU Bu-Rong who kindly provide us the human fibrosarcoma cell line HT1080 and normal human lung embryonic cell line MRC-5.

Author information

Authors and Affiliations

  1. Key Laboratory of Neutronics and Radiation Safety, Institute of Nuclear Energy Safety Technology, Chinese Academy of Sciences, Hefei, 230031, China

    Hui Liu & Chu-Feng **

  2. Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

    Sheng-Fang Ge

  3. Key Laboratory of Ion Beam Bioengineering, Institute of Technical Biology and Agriculture Engineering, Chinese Academy of Sciences, Hefei, 230031, China

    Li-Jun Wu

Authors
  1. Hui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chu-Feng **
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sheng-Fang Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li-Jun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hui Liu.

Additional information

This study was supported by National Magnetic Confinement Fusion Science Program of China (No. 2014GB112006), National Natural Science Foundation of China (No. 11305204) and Natural Science Foundation of Anhui Province of China (No. 1508085SME220).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, H., **, CF., Ge, SF. et al. Antitumor and radiosensitization effect of 12C6+ heavy-ion irradiation mediated by radiation-inducible gene therapy. NUCL SCI TECH 27, 18 (2016). https://doi.org/10.1007/s41365-016-0021-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s41365-016-0021-x

Keywords

Search

Navigation