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Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells

Gene Therapy volume 15, pages 1233–1239 (2008)Cite this article

Abstract

Oncolytic adenoviruses are a promising tool in cancer therapy. In this study, we characterized the role of autophagy in oncolytic adenovirus-induced therapeutic effects. OBP-405, an oncolytic adenovirus regulated by the human telomerase reverse transcriptase promoter (hTERT-Ad, OBP-301) with a tropism modification (RGD) exhibited a strong antitumor effect on glioblastoma cells. When autophagy was inhibited pharmacologically, the cytotoxicity of OBP-405 was attenuated. In addition, autophagy-deficient Atg5−/− mouse embryonic fibroblasts (MEFs) were less sensitive than wild-type MEFs to OBP-405. These findings indicate that OBP-405-induced autophagy is a cell killing effect. Moreover, autophagy-inducing therapies (temozolomide and rapamycin) synergistically sensitized tumor cells to OBP-405 by stimulating the autophagic pathway without altering OBP-405 replication. Mice harboring intracranial tumors treated with OBP-405 and temozolomide survived significantly longer than those treated with temozolomide alone, and mice treated with OBP-405 and the rapamycin analog RAD001 survived significantly longer than those treated with RAD001 alone. The observation that autophagy inducers increase OBP-405 antitumor activity suggests a novel strategy for treating patients with glioblastoma.

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Acknowledgements

We thank Dr Noboru Mizushima for the GFP-LC3 expression vector and the wild-type and Atg5−/− MEFs. We also thank E Faith Hollingsworth for technical support and Elizabeth L Hess for editing the manuscript. This work was supported in part by Grant CA-088936 from the National Cancer Institute (to S Kondo), by a generous donation from the Anthony D Bullock III Foundation (to Y Kondo, R Sawaya and S Kondo) and the Institutional Core Grant CA-16672 High Resolution Electron Microscopy Facility, MD Anderson Cancer Center.

Grant support: This study was supported in part by National Cancer Institute Grants CA088936 and CA108558, a start-up fund from The University of Texas MD Anderson Cancer Center (SK), a generous donation from the Anthony D Bullock III Foundation (YK, RS and SK) and the cancer center support grant (CCSG)/shared resources of MD Anderson Cancer Center.

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Author notes

  1. T Yokoyama and E Iwado: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    T Yokoyama, E Iwado, Y Kondo, H Aoki, R Sawaya & S Kondo

  2. Department of Neuro–Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y Hayashi & M M Georgescu

  3. Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA

    R Sawaya & S Kondo

  4. Department of Biostatistics and Applied Mathematics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K R Hess

  5. Department of Molecular Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G B Mills

  6. Oncolys BioPharma Inc., Tokyo, Japan

    H Kawamura, Y Hashimoto, Y Urata & T Fujiwara

  7. Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

    T Fujiwara

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  1. T Yokoyama
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Corresponding author

Correspondence to T Yokoyama.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Yokoyama, T., Iwado, E., Kondo, Y. et al. Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells. Gene Ther 15, 1233–1239 (2008). https://doi.org/10.1038/gt.2008.98

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