1. ¹Department of Urology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242-1089, USA
2. ²Prostate Cancer Research Group, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242-1089, USA
3. ³Interdisciplinary Graduate Program in Immunology, University of IowaM, 200 Hawkins Drive, Iowa City, IA 52242-1089, USA
4. ⁴The Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242-1089, USA

Correspondence: Thomas S. Griffith, Department of Urology, 3204 MERF, University of Iowa, 375 Newton Road, Iowa City, IA 52242-1089, USA. Fax: +1 (319) 353 4556. E-mail: thomas-griffith@uiowa.edu

Received 16 June 2004; Accepted 7 December 2004.

Abstract

TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis in various tumor cell types and is under investigation as a cancer therapeutic. The development of a recombinant adenovirus encoding the full-length human TRAIL gene (Ad5-TRAIL) replaces the need for large quantities of soluble TRAIL protein in tumor suppressive therapies. However, the full potential of Ad5-TRAIL has not yet been maximized. Recent investigation of a histone deacetylase inhibitor, depsipeptide (FR901228), has demonstrated that it increases cellular susceptibility to adenovirus infection and augments adenoviral transgene expression. Thus, studies were initiated to evaluate the ability of depsipeptide to enhance the cytotoxic activity of Ad5-TRAIL against human prostate tumor cells. In vitro, depsipeptide increased expression of coxsackie–adenovirus receptor, leading to increased adenoviral infection and transgene expression. Additionally, tumor cell killing by Ad5-TRAIL was higher following depsipeptide pretreatment. More surprisingly, depsipeptide also increased prostate tumor cell sensitivity to TRAIL-induced apoptosis. Investigation into the mechanism responsible for increased TRAIL responsiveness revealed increased levels of TRAIL-R1 and -R2 in membrane lipid rafts following depsipeptide treatment. These results indicate that depsipeptide is a potent agent for enhancing the activity of Ad5-TRAIL by multiple mechanisms, allowing for a more efficient use of Ad5-TRAIL as an antitumor therapy.