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

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.

Cellular metabolism dictates T cell effector function in health and disease

“…This occurs upon interferon beta (IFN-β) stimulation at normoxia. 98 Recently, it was demonstrated that hypoxia is a key factor in tumour development as chronic hyperoxia (60% O 2 ) prevents development of pulmonary tumours and prevents tumour metastasis. This effect was closely associated with abrogated CD4, CD8 and natural killer (NK) cell levels suggesting that oxygen levels are crucial for immune cell differentiation and activity.…”

“…Under normoxia, lactate does not prevent MAVS from binding RIG‐I, which is then free to induce histone demethylase activity by activating lysine (K)‐specific demethylase (KDM) 6A (KDM6A) and KDM5A. This occurs upon interferon beta (IFN‐β) stimulation at normoxia 98 . Recently, it was demonstrated that hypoxia is a key factor in tumour development as chronic hyperoxia (60% O 2 ) prevents development of pulmonary tumours and prevents tumour metastasis.…”

Oncolytic Virotherapy in Solid Tumors: The Challenges and Achievements

“…Histone deacetylase inhibitors (HDIs) are recently entered the clinic as a promising treatment for cancers [ 285 ]. The companion of HDIs with OVT increases viral replication, upregulates the transgene expression (such as GM-CSF in T-VEC), enhances virus spread through the tumor cells, and augments oncolytic activities [ 286 , 287 ]. Moreover, HDIs induce antitumor immunity by inducing the expression of NK cell activating ligands and expression of TAAs, resulting NK cells and CTLs priming [ 286 ].…”

An Updated Review of the Epigenetic Mechanism Underlying the Pathogenesis of Age-related Macular Degeneration

“…Most of the HDACis have a broad spectrum of HDAC inhibition; only a few HDACis target relatively specific HDACs; the important point is that some HDACis not only inhibit HDAC activity, but also target many non-histone proteins. Therefore, HDACi application is being studied for the treatment of a wide variety of human diseases, including eye diseases [ 61 , 107 - 111 ]. One example is SIRT1 (class III HDAC); as mentioned previously, stimulation of SIRT1 by resveratrol significantly promoted GFAP, anti-angiogenic PEDF, and TSP-1 expression in the cells as well as in the phagocytic activities [ 111 ].…”