Histone Deacetylase Inhibitors Enhance Cell Killing and Block Interferon-Beta Synthesis Elicited by Infection with an Oncolytic Parainfluenza Virus.

Candace R Fox,Griffith D Parks

doi:10.3390/v11050431

Abstract

Previous results have shown that infection with the cytoplasmic-replicating parainfluenza virus 5 mutant P/V-CPI- sensitizes cells to DNA damaging agents, resulting in the enhanced killing of airway cancer cells. Here, we have tested the hypothesis that histone deacetylase (HDAC) inhibitors can also act with P/V-CPI- infection to enhance cancer cell killing. Using human small cell lung cancer and laryngeal cancer cell lines, 10 HDAC inhibitors were tested for their effect on viability of P/V-CPI- infected cells. HDAC inhibitors such as scriptaid enhanced caspase-3/7, -8 and -9 activity induced by P/V-CPI- and overall cell toxicity. Scriptaid-mediated enhanced killing was eliminated in lung cancer cells that were engineered to express a protein which sequesters double stranded RNA. Scriptaid also enhanced cancer cell killing by two other negative strand RNA viruses – the La Crosse virus and vesicular stomatitis virus. Scriptaid treatment enhanced the spread of the P/V-CPI- virus through a population of cancer cells, and suppressed interferon-beta induction through blocking phosphorylation and nuclear translocation of Interferon Regulatory Factor 3 (IRF-3). Taken together, these data support a role for combinations of a cytoplasmic-replicating RNA virus such as the P/V-CPI- mutant along with chemotherapeutic agents.

Highlights

Oncolytic viruses have shown to be promising treatments for human cancers
To determine the effects on cell viability of combining histone deacetylase (HDAC) inhibitors with P/V-CPI- mutant infection, human non-small cell lung cancer H1299 cells were pretreated for 12 h with dimethyl sulfoxide (DMSO) as a vehicle control, or with various concentrations of either SAHA or scriptaid
We have previously shown that infection with the cytoplasmic-replicating RNA virus P/V-CPI-can sensitize airway cancer cells to chemotherapeutic DNA damaging agents through the modulation of DNA damage response pathways [26]

Summary

Introduction

Oncolytic viruses have shown to be promising treatments for human cancers. FDA approval of a modified herpes simplex virus type 1 for the treatment of advanced malignant melanoma [1], and the number of recombinant viruses in development are evidence of strong interest in these therapies for a variety of cancers [2,3]. Wild type (WT) PIV5 is inherently non-cytopathic and is a poor inducer of host cell responses in most human cell types [11,12,13,14], and would not be expected to have appropriate oncolytic properties. Non-cytopathic WT PIV5 can be converted into a virus that induces cell killing through engineered substitutions in the viral P/V gene [15,16].

Methods

Results

Conclusion