Tamoxifen improves cytopathic effect of oncolytic adenovirus in primary glioblastoma cells mediated through autophagy

Abstract

// Ilya V. Ulasov 1, 4 , Nameeta Shah 1 , Natalya V. Kaverina 2, 5 , Hwahyang Lee 1 , Biaoyang Lin 1 , Andre Lieber 3 , Zaira G. Kadagidze 2 , Jae-Guen Yoon 1 , Brett Schroeder 1 , Parvinder Hothi 1 , Dhimankrishna Ghosh 1 , Anatoly Y. Baryshnikov 2 , Charles S. Cobbs 1 1 Swedish Neuroscience Institute, Seattle, WA, 98122, USA 2 NN. Blokhin Cancer Research Center, RAMN, Moscow, Russia, 115478 3 University of Washington, Seattle, WA, 98122, USA 4 Institute of Experimental Diagnostic and Biotherapy, NN. Blokhin Cancer Research Center, RAMN, Moscow, Russia, 115478 5 Current address: Division of Nephrology, University of Washington, Seattle, 98109, USA Correspondence to: Ilya V. Ulasov, e-mail: Ilya.Ulasov@Swedish.org Charles S. Cobbs, e-mail: Charles.Cobbs@Swedish.org Keywords: brain tumor, adenovirus, survivin, CRAd, autophagy Received: August 05, 2014      Accepted: December 11, 2014      Published: March 02, 2015 ABSTRACT 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.