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In vitro efficacy of AdTRAIL gene therapy of bladder cancer is enhanced by trichostatin A-mediated restoration of CAR expression and downregulation of cFLIP and Bcl-XL

Cancer Gene Therapy volume 13, pages 281–289 (2006)Cite this article

Abstract

Current therapies for bladder cancer are suboptimal and adenoviral gene therapy has been explored as an alternative treatment. In this study, we evaluated the in vitro efficacy of an adenovirus expressing TNF-related apoptosis-inducing ligand (AdTRAIL). At low concentrations of virus, T24 cells were more resistant to AdTRAIL-induced apoptosis than 5637 bladder carcinoma cells. Resistance in T24 cells correlated with poor infectivity and lack of surface expression of coxsackie and adenovirus receptor (CAR). Pretreatment with low concentrations of the histone deacetylase inhibitor trichostatin A, restored CAR expression in T24 cells, which facilitated viral infection and resulted in apoptosis at low concentrations of AdTRAIL. In addition, trichostatin A reduced the expression of Bcl-XL and cFLIP resulting in increased sensitivity to recombinant TRAIL. Overexpression of cFLIP inhibited TRAIL-mediated killing in trichostatin A pretreated cells, indicating that downregulation of this antiapoptotic protein is required for sensitization. Therefore, trichostatin A can enhance the efficacy of AdTRAIL by restoring CAR expression and by generating a more pro-apoptotic phenotype that would facilitate bystander activity of TRAIL. Combination of histone deacetylase inhibitors with intravesical AdTRAIL gene therapy may be a novel treatment strategy for bladder cancer.

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Acknowledgements

We thank Dr Marcus Peter for his generous supply of NF-6 antibody, Dr Harald Wajant for the plasmids expressing the c-FLIP-GFP fusion proteins and Mr Rick Peppler of the MUSC flow cytometry facility for excellent technical assistance. This work was supported by a grant from the Department of Defense (N6311602MD200) and the MUSC-HSF Brockmann fund awarded to CVJ.

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  1. Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA

    A El-Zawahry, P Lu, S J White & C Voelkel-Johnson

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  1. A El-Zawahry
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Correspondence to C Voelkel-Johnson.

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El-Zawahry, A., Lu, P., White, S. et al. In vitro efficacy of AdTRAIL gene therapy of bladder cancer is enhanced by trichostatin A-mediated restoration of CAR expression and downregulation of cFLIP and Bcl-XL. Cancer Gene Ther 13, 281–289 (2006). https://doi.org/10.1038/sj.cgt.7700905

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