Tamoxifen improves cytopathic effect of oncolytic adenovirus in primary glioblastoma cells mediated through autophagy.
Oncolytic gene therapy using viral vectors may provide an attractive therapeutic option for malignant gliomas. These viral vectors are designed in a way to selectively target tumor cells and spare healthy cells. To determine the translational impact, it is imperative to assess the factors that interfere with the anti-glioma effects of the oncolytic adenoviral vectors. In the current study, we evaluated the efficacy of survivin-driven oncolytic adenoviruses pseudotyping with adenoviral fiber knob belonging to the adenoviral serotype 3, 11 and 35 in their ability to kill glioblastoma (GBM) cells selectively without affecting normal cells. Our results indicate that all recombinant vectors used in the study can effectively target GBM in vitro with high specificity, especially the 3 knob-modified vector. Using intracranial U87 and U251 GBM xenograft models we have also demonstrated that treatment with Conditionally Replicative Adenovirus (CRAd-S-5/3) vectors can effectively regress tumor. However, in several patient-derived GBM cell lines, cells exhibited resistance to the CRAd infection as evident from the diminishing effects of autophagy. To improve therapeutic response, tumor cells were pretreated with tamoxifen. Our preliminary data suggest that tamoxifen sensitizes glioblastoma cells towards oncolytic treatment with CRAd-S-5/3, which may prove useful for GBM in future experimental therapy.
Swedish Neuroscience Institute, Seattle, WA, 98122, USA.|Institute of Experimental Diagnostic and Biotherapy, NN. Blokhin Cancer Research Center, RAMN, Moscow, Russia, 115478.
Ilya V
IV
Ulasov
Swedish Neuroscience Institute, Seattle, WA, 98122, USA.
Nameeta
N
Shah
NN. Blokhin Cancer Research Center, RAMN, Moscow, Russia, 115478.|Current address: Division of Nephrology, University of Washington, Seattle, 98109, USA.
Natalya V
NV
Kaverina
Swedish Neuroscience Institute, Seattle, WA, 98122, USA.
Hwahyang
H
Lee
Swedish Neuroscience Institute, Seattle, WA, 98122, USA.
Biaoyang
B
Lin
University of Washington, Seattle, WA, 98122, USA.
Andre
A
Lieber
NN. Blokhin Cancer Research Center, RAMN, Moscow, Russia, 115478.
Zaira G
ZG
Kadagidze
Swedish Neuroscience Institute, Seattle, WA, 98122, USA.
Jae-Guen
JG
Yoon
Swedish Neuroscience Institute, Seattle, WA, 98122, USA.
Brett
B
Schroeder
Swedish Neuroscience Institute, Seattle, WA, 98122, USA.
Parvinder
P
Hothi
Swedish Neuroscience Institute, Seattle, WA, 98122, USA.
Dhimankrishna
D
Ghosh
NN. Blokhin Cancer Research Center, RAMN, Moscow, Russia, 115478.
Anatoly Y
AY
Baryshnikov
Swedish Neuroscience Institute, Seattle, WA, 98122, USA.
Charles S
CS
Cobbs
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D006801:Humans; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods*; D013629:Tamoxifen / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen