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

T. Yokoyama, E. Iwado, Y. Kondo, H. Aoki, Y. Hayashi, M. M. Georgescu, R. Sawaya, K. R. Hess, G. B. Mills, H. Kawamura, Y. Hashimoto, Y. Urata, T. Fujiwara, S. Kondo

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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.

Original languageEnglish
Pages (from-to)1233-1239
Number of pages7
JournalGene Therapy
Volume15
Issue number17
DOIs
Publication statusPublished - Jun 27 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Yokoyama, T., Iwado, E., Kondo, Y., Aoki, H., Hayashi, Y., Georgescu, M. M., Sawaya, R., Hess, K. R., Mills, G. B., Kawamura, H., Hashimoto, Y., Urata, Y., Fujiwara, T., & Kondo, S. (2008). Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells. Gene Therapy, 15(17), 1233-1239. https://doi.org/10.1038/gt.2008.98