Abstract
Epigenetic therapies such as histone deacetylase inhibitors (HDACi) not only have the capability to decrease tumor cell proliferation and to induce tumor cell death but also to silence antiviral response genes. Here, we investigated whether the combination of an oncolytic measles vaccine virus (MeV) with the novel oral HDACi resminostat (Res), being in clinical testing in patients with hepatocellular carcinoma (HCC), results in an enhanced efficacy of this epi-virotherapeutic approach compared to any of the two corresponding monotherapies. When testing a panel of human hepatoma cell lines, we found (i) a significantly improved rate of primary infections when using oncolytic MeV under concurrent treatment with resminostat, (ii) a boosted cytotoxic effect of the epi-virotherapeutic combination (Res + MeV) with enhanced induction of apoptosis, and, quite importantly, (iii) an absence of any resminostat-induced impairment of MeV replication and spread. Beyond that, we could also show that (iv) resminostat, after hepatoma cell stimulation with exogenous human interferon (IFN)-β, is able to prevent the induction of IFN-stimulated genes, such as IFIT-1. This finding outlines the possible impact of resminostat on cellular innate immunity, being instrumental in overcoming resistances to MeV-mediated viral oncolysis. Thus, our results support the onset of epi-virotherapeutic clinical trials in patients exhibiting advanced stages of HCC.
Highlights
In response to viral pathogens, mammalian cells have developed an arsenal of innate immunity factors to prevent viral infections, with a central role assigned to the interferon (IFN) system.[1]
We have tested the antitumoral potency of either resminostat, a novel oral histone deacetylase inhibitors (HDACi),[25] or MeVsuper-cytosine deaminase (SCD), a prototypic suicide gene-armed measles vaccine virotherapeutic,[11] in a commonly used panel of human hepatoma cell lines (HepG2, Hep3B, PLC/PRF/5)
Antitumoral activities of resminostat and measles virus (MeV) on human hepatoma cell lines Combinations of various epigenetic compounds with oncolytic viruses have been shown to result in the enhancement of therapeutic efficacy, encouraging further investigation of novel combinatorial a PLC/PRF/5
Summary
In response to viral pathogens, mammalian cells have developed an arsenal of innate immunity factors to prevent viral infections, with a central role assigned to the interferon (IFN) system.[1]. In this context, we have tested the antitumoral potency of either resminostat, a novel oral HDACi,[25] or MeVsuper-cytosine deaminase (SCD), a prototypic suicide gene-armed measles vaccine virotherapeutic,[11] in a commonly used panel of human hepatoma cell lines (HepG2, Hep3B, PLC/PRF/5). We investigated the monotherapeutic cytotoxic potential of resminostat on human hepatoma cell lines For this purpose, HepG2, Hep3B, and PLC/PRF/5 cells were incubated for 96 hours with increasing concentrations of resminostat Virotherapeutic approach when compared to any of the two corresponding monotherapies
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