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A combinatory use of adenoviruses expressing melanoma differentiation-associated gene-7 and replication-competent adenoviruses produces synergistic effects on pancreatic carcinoma cells

  • Research Article
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Tumor Biology

Abstract

Type 5 adenoviruses expressing mda-7 gene (Ad-mda-7) induced cell death in various kinds of human tumors, but pancreatic carcinoma cells were relatively resistant to Ad-mda-7-mediated cytotoxicity. We then examined whether infection of Ad-mda-7 together with replication-competent Ad produced combinatory cytotoxic effects. We prepared replication-competent Ad, defective of the E1B55kDa gene or activated by a transcriptional regulatory region of the midkine or the survivin gene of which the expression was up-regulated in human tumors. Type 5 Ad bearing the exogenous regulatory region were further modified by replacing the fiber-knob region with that of type 35 Ad. Pancreatic carcinoma cells were infected with replication-incompetent Ad-mda-7 and the replication-competent Ad. Combinatory effects were examined with the CalcuSyn software and cell cycle analyses. Ad-mda-7 and the replication-competent Ad achieved cytotoxicity to pancreatic carcinoma. A combinatory use of Ad-mda-7 and either Ad defective of the E1B55kDa gene or Ad activated by the regulatory region produced synergistic cytotoxic effects. Cell cycle analyses demonstrated that the combination increased sub-G1 populations. These data collectively suggest that expression of MDA-7 augments cytotoxicity of replication-competent Ad and achieves adjuvant effects on Ad-mediated cell death.

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Abbreviations

Ad:

Adenoviruses

Ad-delE1B55:

Ad defective of E1B55kDa molecules

Ad-mda-7:

Ad expressing the mda-7 gene

Ad-LacZ:

Ad expressing the β-galactosidase gene

AdF:

Type 5 Ad bearing type 35-derived fiber-knob region

AdF-MK:

AdF in which E1 gene is activated by MK regulatory region

AdF-Sur:

AdF in which E1 gene is activated by Sur regulatory region

AdF-LacZ:

AdF expressing the β-galactosidase gene

CAR:

Coxsakie adenovirus receptor

CI:

Combination index

Fa:

Fractions affected

IL:

Interleukin

MDA-7:

Melanoma differentiation-associated gene-7

MK:

Midkine

ROS:

Reactive oxygen species

Sur:

Survivin

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Acknowledgments

This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Grant-in-Aid for Research on seeds for Publicly Essential Drugs and Medical Devices from the Ministry of Health, Labor and Welfare of Japan, and a Grant-in-Aid from the Nichias Corporation.

Conflicts of interest

The authors declare that there is no conflict of interests in this research.

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    Authors and Affiliations

    1. Department of Hematology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China

      Guangyu Ma & Boya Zhong

    2. Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan

      Boya Zhong, Shinya Okamoto, Yuanyuan Jiang, Kiyoko Kawamura, Hongdan Liu & Masatoshi Tagawa

    3. Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan

      Shinya Okamoto, Yuji Tada & Koichiro Tatsumi

    4. Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan

      Boya Zhong, Yuanyuan Jiang & Masatoshi Tagawa

    5. Department of Immunology, Hebei Medical University, Shijiazhuang, China

      Quanhai Li

    6. Cell Therapy Center, The First Hospital of Hebei Medical University, Shijiazhuang, China

      Quanhai Li

    7. Department of Thoracic Diseases, Chiba Cancer Center, Chiba, Japan

      Masato Shingyoji & Ikuo Sekine

    8. Department of Surgery, School of Medicine, Toho University, Tokyo, Japan

      Hideaki Shimada

    9. Department of Pathology, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, Japan

      Kenzo Hiroshima

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    1. Guangyu Ma
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    2. Boya Zhong
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    3. Shinya Okamoto
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    Corresponding author

    Correspondence to Masatoshi Tagawa.

    Additional information

    Guangyu Ma and Boya Zhong contributed equally to this work.

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    Ma, G., Zhong, B., Okamoto, S. et al. A combinatory use of adenoviruses expressing melanoma differentiation-associated gene-7 and replication-competent adenoviruses produces synergistic effects on pancreatic carcinoma cells. Tumor Biol. 36, 8137–8145 (2015). https://doi.org/10.1007/s13277-015-3555-3

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    • DOI: https://doi.org/10.1007/s13277-015-3555-3

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