Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death.
The eradication of brain tumor stem cells is essential for long-term brain tumor remission after treatment. In this study, we examined the therapeutic potential of an oncolytic adenovirus, Delta-24-RGD, targeted to the abnormal p16INK4/Rb pathway in brain tumor stem cells. Four brain tumor stem cell lines from surgical glioblastoma specimens expressed high levels of adenoviral receptors and allowed for efficient viral infection, replication, and oncolysis in an Rb-dependent manner. Delta-24-RGD induced autophagic cell death, as indicated by accumulation of Atg5 and LC3-II protein and autophagic vacuoles. Treatment of xenografts derived from brain tumor stem cells with Delta-24-RGD statistically significantly improved the survival of glioma-bearing mice (means: 38.5 versus 66.3 days, difference = 27.8 days, 95% confidence interval = 19.5 to 35.9 days, P <.001). Analyses of treated tumors showed that Atg5 expression colocalized with viral fiber protein and delineated a wave front of autophagic cells that circumscribed areas of virally induced necrosis. Our results show for the first time that brain tumor stem cells are susceptible to adenovirus-mediated cell death via autophagy in vitro and in vivo.
Jiang
Hong
H
Brain Tumor Center, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. hjiang@mdanderson.org
Gomez-Manzano
Candelaria
C
Aoki
Hiroshi
H
Alonso
Marta M
MM
Kondo
Seiji
S
McCormick
Frank
F
Xu
Jing
J
Kondo
Yasuko
Y
Bekele
B Nebiyou
BN
Colman
Howard
H
Lang
Frederick F
FF
Fueyo
Juan
J
D000256:Adenoviridae; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D019942:Genes, p16 / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D014411:Neoplastic Stem Cells; D050130:Oncolytic Virotherapy / Q000379:methods*; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D014408:Biomarkers, Tumor; D008869:Microtubule-Associated Proteins