Cytotoxic effects of NF-κB inhibitors in combination with anti-herpes agents on Epstein-Barr virus-positive gastric carcinoma in vitro

Abstract

Epstein-Barr virus (EBV) infection in tumor cells is usually restricted to the latent form, indicating that the induction of viral lytic infection may present a novel approach for the treatment of EBV-associated tumors. By contrast, EBV lytic replication is inhibited by high-levels of nuclear factor (NF)-κB, which suggests that NF-κB inhibitors may activate lytic replication from the latent form. In the current study, the addition of NF-κB inhibitors (Bay11-7082, Z-LLF-CHO and aspirin) was observed to induce the EBV lytic genes BZLF1, BRLF1 and BMRF1 in EBV-positive gastric cancer (GC) cells. Both EBV-positive and -negative GC cells were treated with different concentrations of anti-herpes agents and the cytotoxic effects were measured at different time points following induction of EBV lytic replication. A marginal dose-and time-dependent reduction in cell viability was observed for EBV-positive and-negative GC cells. The cytotoxic effects of NF-κB inhibitors on EBV-positive GC cells were enhanced by the addition of the anti-herpes agents, ganciclovir, acyclovir, foscarnet and brivudine (P<0.05). However, there was no significant synergistic effect on EBV-negative GC cells. The combination of 5 mM aspirin and ganciclovir exhibited the highest cytotoxic effect in EBV-positive GC cells (CC50=7.2 μg/ml).