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Replication-competent adenoviruses with the type 35-derived fiber-knob region achieve reactive oxygen species-dependent cytotoxicity and produce greater toxicity than those with the type 5-derived region in pancreatic carcinoma

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Abstract

Pancreatic carcinoma is relatively resistant to chemotherapy and cell death induced by replication of adenoviruses (Ad) can be one of the therapeutic options. Transduction efficacy of conventional type 5 Ad (Ad5) is however low and the cytotoxic mechanism by replication-competent Ad was not well understood. We constructed replication-competent Ad5 of which the E1A promoter region was replaced with a transcriptional regulatory region of the midkine, the survivin or the cyclooxygenase-2 gene, all of which were expressed at a high level in human tumors. We also prepared replication-competent Ad5 that were activated with the same region but had the type 35 Ad-derived fiber-knob region (AdF35) to convert the major cellular receptor for Ad infection from the coxsackie adenovirus receptor to CD46 molecules. Replication-competent AdF35 that were activated with the exogenous region produced cytotoxic effects on human pancreatic carcinoma cells greater than the corresponding Ad5 bearing with the same regulatory region. Cells infected with the AdF35 showed cytopathic effects and increased sub-G1 fractions. Caspase-9, less significantly caspase-8 and poly (ADP-ribose) polymerase, but not caspase-3 was cleaved and expression of molecules involved in autophagy and caspase-independent cell death pathways remained unchanged. Nevertheless, H2A histone family member X molecules were phosphorylated, and N-acetyl-l-cystein, an inhibitor for reactive oxygen species, suppressed the AdF35-mediated cytotoxicity. These data indicated a novel mechanism of Ad-mediated cell death and suggest a possible clinical application of the fiber-knob modified Ad.

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Abbreviations

Ad:

Adenoviruses

Sur:

Survivin

MK:

Midkine

COX-2:

Cyclooxygenase-2

Ad5:

Type 5 adenoviruses

CAR:

Coxsackie adenovirus receptor

AdF35:

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

ROS:

Reactive oxygen species

CMV:

Cytomegalovirus

GFP:

Green fluorescent protein

Lac:

β-galactosidase

Vp:

Virus particles

MOI:

Multiplicity of infection

NAC:

N-acetyl-l-cysteine

PARP:

Poly (ADP-ribose) polymerase

H2AX:

H2A histone family member X

IC50 :

Half maximal inhibitory concentration

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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.

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Authors and Affiliations

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

    Suguru Yamauchi, Kiyoko Kawamura, Shinya Okamoto, Takao Morinaga, Yuanyuan Jiang & Masatoshi Tagawa

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

    Suguru Yamauchi, Yuanyuan Jiang & Masatoshi Tagawa

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

    Shinya Okamoto, Takao Morinaga, Yuji Tada & Koichiro Tatsumi

  4. Division of Respirology, Chiba Cancer Center, Chiba, Japan

    Masato Shingyoji & Ikuo Sekine

  5. Department of Genetics, Hyogo College of Medicine, Nishinomiya, Japan

    Shuji Kubo

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

    Hideaki Shimada

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

    Kenzo Hiroshima

Authors
  1. Suguru Yamauchi
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  2. Kiyoko Kawamura
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  3. Shinya Okamoto
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  4. Takao Morinaga
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  5. Yuanyuan Jiang
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  6. Masato Shingyoji
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  7. Ikuo Sekine
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  8. Shuji Kubo
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  9. Yuji Tada
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  10. Koichiro Tatsumi
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  11. Hideaki Shimada
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  12. Kenzo Hiroshima
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  13. Masatoshi Tagawa
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Corresponding author

Correspondence to Masatoshi Tagawa.

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Yamauchi, S., Kawamura, K., Okamoto, S. et al. Replication-competent adenoviruses with the type 35-derived fiber-knob region achieve reactive oxygen species-dependent cytotoxicity and produce greater toxicity than those with the type 5-derived region in pancreatic carcinoma. Apoptosis 20, 1587–1598 (2015). https://doi.org/10.1007/s10495-015-1171-8

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  • DOI: https://doi.org/10.1007/s10495-015-1171-8

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