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

Mol Med Rep. 2016 Sep;14(3):2359-67. doi: 10.3892/mmr.2016.5496. Epub 2016 Jul 11.

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).

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antiviral Agents / pharmacology*
  • Cell Line, Tumor
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Epstein-Barr Virus Infections / complications*
  • Epstein-Barr Virus Infections / virology
  • Gene Expression
  • Herpesvirus 4, Human / drug effects*
  • Humans
  • NF-kappa B / antagonists & inhibitors*
  • Stomach Neoplasms / etiology*
  • Stomach Neoplasms / metabolism*
  • Transcription Factor RelA / antagonists & inhibitors
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Transcription Factor RelB / antagonists & inhibitors
  • Transcription Factor RelB / genetics
  • Transcription Factor RelB / metabolism
  • Virus Activation / drug effects
  • Virus Replication / drug effects

Substances

  • Antineoplastic Agents
  • Antiviral Agents
  • NF-kappa B
  • Transcription Factor RelA
  • Transcription Factor RelB