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

Correspondence: Dr C Voelkel-Johnson, Department of Microbiology & Immunology, Medical University of SC, PO Box 250504, 173 Ashley Ave, Charleston, SC 29403, USA. E-mail: johnsocv@musc.edu

Received 9 April 2005; Revised 14 June 2005; Accepted 10 July 2005; Published online 16 September 2005.

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-X_L 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.