Combination therapy of conditionally replicating adenovirus and histone deacetylase inhibitors

Abstract

Abstract. Combination therapy of adenoviral gene therapy and a histone deacetylase (HDAC) inhibitor is important due to the enhancing effect of HDAC inhibitors on adenoviral transduction and transcription. However, contradictory results have been reported on the effect of combination of CRAd (conditionally replicating adenovirus) and HDAC inhibitors. This study was designed to investigate the interaction of CRAd and HDAC inhibitors and determine the ideal way to combine the two agents. Combination of HDAC inhibitors (SK7041, SBHA and vorinostat) at pre-and post-transductional periods with CRAd enhanced the transduction of CRAd and expression of luciferase expression from Δ24-luc in vitro. However, suppression of luciferase expression from Δ24-luc injected tumor mass was observed by in vivo tumor bioluminescence imaging and drug interaction analysis also showed an antagonistic interaction that was probably related with the inhibitory effect of the HDAC inhibitor on adenoviral replication. Suppression of p21 induction by p21 siRNA reversed the suppressive effect of vorinostat on the replication of CRAd, but still failed to reverse the antagonistic interaction. Addition of vorinostat at the pre-transductional period revealed an improvement in the transduction efficiency of CRAd and also induced a synergistic interaction between CRAd and vorinostat, which was possibly related with prevention of the suppressive effect of vorinostat on adenoviral replication. In conclusion, the addition of HDAC inhibitor before CRAd injection showed synergistic antitumor effects, which warrants further investigation on the sequence of HDAC inhibitor and CRAd treatment in an animal tumor model.

GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment

“…Our findings demonstrated that both HDACi (SBHA and MS-275) pretreatment elevated CAR expression levels ( Figure 2 a) and membrane attachment of Ad to the surface of the cancer cell membrane ( Figure 2 b and Figure S5 ), in line with several other reports demonstrating that HDACi-treated cells show elevated CAR or αvβ3 integrin expression levels, that enhance cell internalization and transgene expression of Ad [ 23 , 38 , 39 , 40 ]. Importantly, our study was the first to demonstrate that HDACi treatments also elevated the expression levels of dynamin 2 and clathrin ( Figure S6 ), which are critical to clathrin-mediated endocytosis of Ad after Ad capsids are docked to CAR and integrin expressed on the cell surface [ 33 ].…”

The HDAC Inhibitors Scriptaid and LBH589 Combined with the Oncolytic Virus Delta24-RGD Exert Enhanced Anti-Tumor Efficacy in Patient-Derived Glioblastoma Cells

“…[ 9 , 10 ] These drugs also affect non-histone targets including genes involved in cell cycle regulation, apoptosis and autophagy. [ 9 , 11 ] HDACi are reported to enhance oncolytic adenoviral therapy[ 12 ], however the effects of a panel of HDACi in patient-derived glioblastoma stem-like cells (GSC), a model that recapitulates the original tumor [ 13 ], have not been evaluated yet. Previous studies provide a rationale to systematically investigate the efficacy of HDACi as enhancers for Delta24-RGD in glioblastoma.…”

Inhibition of Histone Deacetylase Activity Aggravates Coxsackievirus B3-Induced Myocarditis by Promoting Viral Replication and Myocardial Apoptosis

“…Coxsackie adenovirus receptor (CAR) is the primary receptor for CVB3 to infect permissive cells. It was reported that HDACI increases the expression of CAR in several cancer cell lines ( 25 , 26 ). To investigate whether HDACI enhanced CVB3 replication by increasing CAR expression and CVB3 entry into cells, cardiac myocytes were treated with SAHA or TSA for various time periods, and CAR expression was determined by Western blotting.…”