β-adrenergic Receptor Inhibition Enhances Oncolytic Herpes Virus Propagation Through STAT3 Activation in Gastric Cancer

Abstract

\n BackgroundOncolytic viruses (OVs) are considered a promising therapeutic alternative for cancer. However, OVs could activate the host innate immunity, then impair the viral propagation in tumor cells. In this study, we explored the effect of propranolol, a non-selective β-blocker , on the antitumor efficacy of T1012G virus in gastric cancer models.Results Cell viability assay detected a 97.9% decrease of T1012G IC50 in HGC-27 when it was pretreated with propranolol along with a 7-fold increase of virus titers compared with T1012G only group (P < 0.001). Moreover, propranolol pretreatment caused sustained tumor regression (335.3± 36.92 mm3 vs. 1118 ± 210.0 mm3, P<0.01) and enhanced the viral propagation (4-fold increase, P < 0.01) compared with T1012G only group. Propranolol pretreatment significantly enhanced the p-STAT3 (2.9-fold, P<0.05) and suppressed p-PKR (65.94% ± 10.11%, P<0.05) compared with T1012G only group. In addition, propranolol could counteract IFN-α/β-mediated inhibition of viral propagation (compared with IFNα: 5.1-fold, P<0.001; IFNβ: 4.6-fold, P<0.01) or enhancement of PKR activation (IFNα: 92.57% ± 1.77%, P<0.001, IFNβ: 99.34%± 0.13% decrease, P<0.001). Conclusions In summary, β-blocker pretreatment could improve the propagation and therapeutic efficacy of T1012G in human gastric cancer by regulating STAT3-PKR signaling cascade, even in the presence of type I IFNs . These data support new strategies of improving the efficacy of OVs in gastric cancer.