Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells.
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.
Yokoyama
T
T
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. tyokoyama@mdanderson.org
Iwado
E
E
Kondo
Y
Y
Aoki
H
H
Hayashi
Y
Y
Georgescu
M M
MM
Sawaya
R
R
Hess
K R
KR
Mills
G B
GB
Kawamura
H
H
Hashimoto
Y
Y
Urata
Y
Y
Fujiwara
T
T
Kondo
S
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001932:Brain Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D005909:Glioblastoma / Q000628:therapy*; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D020123:Sirolimus / Q000627:therapeutic use; D000077204:Temozolomide
D003606:Dacarbazine; D020123:Sirolimus; D000077204:Temozolomide