Low Dose Histone Deacetylase Inhibitor, Depsipeptide (FR901228), Promotes Adenoviral Transduction in Human Rhabdomyosarcoma Cell Lines

Abstract

Purpose. Transduction of rhabdomyosarcoma (RMS) cells with adenoviral vectors for in vivo and in vitro applications has been limited by the low to absent levels of coxackie and adenovirus receptor (CAR). This study investigates the potential use of low doses of a histone deacetylase inhibitor, depsipeptide (FR901228), currently in Phase II human trials, to enhance adenoviral uptake in six rhabdomyosarcoma cell lines. Methods. Differences in adenoviral uptake in the presence and absence of depsipeptide (FR901228) were assessed using an adenoviral construct tagged with green fluorescent protein. Changes in CAR and a v integrin expression RMS in response to pretreatment with depsipeptide (FR901128) was determined using RT-PCR. Results. Pretreatment of five of six RMS cell lines with 0.5 ng/ml of depsipeptide (FR901228) for 72 h resulted in increased viral uptake as assessed by green fluorescent protein expression. RT-PCR analysis for CAR showed that in four of these five cell lines, CAR expression was increased 2.8-8.1-fold in cells treated with depsipeptide (FR901228) as compared to control. a v integrin expression was substantially increased in the one cell line, RH5, which showed increased GFP expression in response to depsipeptide (FR901228) pretreatment but a minimal increase in CAR expression. Conclusions. Depsipeptide (FR901228) can be used as a vehicle to enhance adenoviral transduction in a majority of RMS cells. The mechanism of increased viral uptake appears to mediate via upregulation of CAR.

Clinical Efficacy of Vorinostat in a Patient with Leiomyosarcoma

“…28 There are limited preclinical data reporting the activity of HDAC inhibitors in sarcoma. [31][32][33][34][35][36][37][38][39] Ecke and co-workers observed that combined 5-aza-2′deoxycytidine (a DNA methylation inhibitor) and valproic acid (a HDAC inhibitor) efficiently prevented medulloblastoma and rhabdomyosarcoma formation in patched mutant mice. 32 Nguyen and co-workers observed that the Hsp90 inhibitor 17-AAG and the HDAC inhibitor MS-275 had synergistic, antiproliferative, and proapoptotic effects on synovial sarcoma in vitro.…”