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Heat-shock protein 90 inhibitors synergistically enhance melanoma differentiation-associated gene-7-mediated cell killing of human pancreatic carcinoma

Cancer Gene Therapy volume 20, pages 663–670 (2013)Cite this article

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Abstract

Pancreatic cancer is one of the intractable diseases and an effective therapeutic strategy is required to improve the prognosis. We examined possible antitumor effects of adenoviruses expressing melanoma differentiation-associated gene-7/interleukin-24 (Ad-mda-7) and a heat-shock protein 90 (Hsp90) inhibitor to human pancreatic carcinoma cells. Ad-mda-7 and an Hsp90 inhibitor, geldanamycin (GA), produced cytotoxic effects, and a combinatory use of Ad-mda-7 and GA further achieved synergistic effects. Administration of N-acetyl-L-cysteine, an inhibitor of reactive oxygen species, eliminated Ad-mda-7- and GA-mediated cytotoxicity. Ad-mda-7 augmented phosphorylated AKT levels but GA did not influence the phosphorylation. GA-treated cells showed cleavage of poly-(ADP-ribose) polymerase but not caspase-3, and upregulated Hsp70 and LC3A/B II levels, whereas Ad-mda-7-treated cells did not. GA treatments augmented ubiquitination and markedly increased melanoma differentiation-associated gene-7 (MDA-7) expression levels. These findings suggest that Ad-mda-7-mediated cytotoxicity is dependent on reactive oxygen species but independent of apoptosis or autophagy, and that GA-mediated cytotoxicity was linked with caspase-independent apoptosis and/or autophagy. A mechanism underlying the combinatory effects of Ad-mda-7 and GA remained complex and the synergism is attributable to multiple factors including increased MDA-7 protein stability by GA.

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Acknowledgements

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, Chuo-ku, Chiba, Japan

    Z Zhang, K Kawamura, Y Jiang, G Ma, Q Li, H Liu & M Tagawa

  2. Department of Gynecology and Obstetrics, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China

    Z Zhang & S Kang

  3. Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan

    Y Jiang, Q Li & M Tagawa

  4. Department of Thoracic Diseases, Chiba Cancer Center, Chuo-ku, Chiba, Japan

    M Shingyoji

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

    G Ma

  6. Department of Immunology, Basic Medical College, Hebei Medical University, Shijiazhuang, China

    Q Li & J Hu

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

    Q Li

  8. Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China

    Y Qi

  9. Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China

    F Zhang

  10. Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China

    B Shan

  11. Department of Endoscopy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China

    S Wang

  12. SVP Translational Medicine, Intrexon Corporation, Germantown, MD, USA

    S Chada

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  1. Z Zhang
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  9. H Liu
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  13. S Wang
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  14. S Chada
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  15. M Tagawa
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Correspondence to M Tagawa.

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Zhang, Z., Kawamura, K., Jiang, Y. et al. Heat-shock protein 90 inhibitors synergistically enhance melanoma differentiation-associated gene-7-mediated cell killing of human pancreatic carcinoma. Cancer Gene Ther 20, 663–670 (2013). https://doi.org/10.1038/cgt.2013.66

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  • DOI: https://doi.org/10.1038/cgt.2013.66

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