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Complementary treatment of siTERT for improving the antitumor effect of TERT-specific I-131 therapy

Cancer Gene Therapy volume 19, pages 263–270 (2012)Cite this article

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Abstract

Sodium iodide symporter (NIS)-based radionuclide therapy provides an effective means of treating malignant tumors. However, it is sometimes inadequate because of limited effects on radio-resistant tumors, and thus, combination therapies with other therapeutic options have been requested to enhance its efficacy. Human telomerase reverse transcriptase (hTERT) has been reported to be involved in the progression of most cancers and also been viewed as a good candidate for targeting tumor. Application of TERT-specific radionuclide therapies using NIS gene transfer have been reported to treat TERT-positive tumors, but this approach only demonstrated tumor regression rather than eradication. As inhibiting TERT expression by introducing the hTERT-specific shRNA (siTERT) has been suggested as a therapeutic option, we investigated the complementary role of siTERT treatment after the TERT-specific I-131 therapy and its possibility as a novel anticancer therapeutic strategy. Retroviruses containing TERT promoter/NIS for TERT specific Radionuclide therapy and siTERT for TERT targeting antisense therapy were produced. Hep3B cells expressing TERT specific NIS (Hep3B-TERT/NIS) were xenografted into nude mouse and visualized with micro-SPECT/CT for monitoring NIS activity. The levels of hTERT mRNA, protein and its activity were confirmed by RT-PCR, Western blotting and Telomerase repeat amplification protocol assay. Cell proliferation was monitored by MTT assay and induced apoptosis was confirmed by Annexin-V-PI staining. Therapeutic effects of I-131 and/or siTERT were evaluated by clonogenic assay and mouse tumor model. Reduction of hTERT mRNA, protein and TERT activity by siTERT were observed in Hep3B-TERT/NIS cells. The viabilities of the infected cells were significantly decreased to 50% versus siScramble treated controls. The early apoptotic cell population was increased by siTERT. The survival rates of cells treated with siTERT or I-131 alone were 72.4±7.6% and 56.2±5.2%, respectively. However, the survival rate of cells treated with I-131 and siTERT were decreased to 22.1±2.8%. From mouse xenograft model, we also found that the siTERT gene therapy showed synergism to the radioiodine therapy for reducing tumor growth in vivo. Our Results suggested that complementary siTERT gene therapy offers a novel strategy of cancer therapy to improve the therapeutic efficacy of TERT-specific I-131.

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Acknowledgements

We gratefully thank Chae-Ok Yun (Yonsei University) for providing 5 mmTERT promoter and acknowledge Hyunjung Kim for assisting virus production. This work was supported by the National Research Foundation of Korea (NRF) funded by the Korean government (Ministry of Education, Science and Technology) Grant No. 20110002308 and 20110002928.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea

    S Kim, H Youn, M G Song, H K Chung, D S Lee & J-K Chung

  2. Department of Tumor Biology, Seoul Naional University College of Medicine, Seoul, Korea

    S Kim, M G Song, H K Chung & J-K Chung

  3. Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

    S Kim, H Youn, M G Song, H K Chung & J-K Chung

  4. Cancer Imaging Center, Seoul National University Cancer Hospital, Seoul, Korea

    H Youn

  5. Laboratory of Molecular Imaging, Korea Institute of Radiological & Medical Sciences, Seoul, Korea

    J H Kang

  6. Department of Molecular Medicine and Biopharmaceutical Science, WCU Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea

    D S Lee

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  1. S Kim
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Correspondence to H Youn or J-K Chung.

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Kim, S., Youn, H., Song, M. et al. Complementary treatment of siTERT for improving the antitumor effect of TERT-specific I-131 therapy. Cancer Gene Ther 19, 263–270 (2012). https://doi.org/10.1038/cgt.2011.88

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