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

• Published in: Gene therapy Vol. 15; no. 17; pp. 1233 - 1239
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-09-2008; Nature Publishing Group
• Subjects: Adenoviridae - genetics; Adenovirus; Adenoviruses; Animals; Antitumor activity; Autophagy; Autophagy - drug effects; Biomedical and Life Sciences; Biomedicine; Brain cancer; Brain Neoplasms - therapy; Cancer; Cell Biology; Cell Line, Tumor; Cellular biology; Cytotoxicity; Dacarbazine - analogs & derivatives; Dacarbazine - therapeutic use; Embryo fibroblasts; Gene Expression; Gene Therapy; Genetic Therapy - methods; Glioblastoma; Glioblastoma - therapy; Glioblastoma cells; Human Genetics; Mice; Nanotechnology; Oncolysis; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Rapamycin; RNA-directed DNA polymerase; Rodents; short-communication; Sirolimus - therapeutic use; Telomerase; Telomerase reverse transcriptase; Temozolomide; Tropism; Tumor cells; Viruses; OBP-405; autophagy; glioblastoma; OBP-301
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2008.98

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.