Drugs That Mimic Hypoxia Selectively Target EBV-Positive Gastric Cancer Cells

SIMPLE SUMMARY: Epstein-Barr virus (EBV) infects greater than 90% of the world’s population and remains in infected people for their lifetime, mostly in a latent form of infection. In some people, latent EBV infection leads to cancer, including EBV-associated gastric carcinomas. Lytic-induction therapy involves switching EBV from a latent to lytic form of infection so that replicating EBV can then kill EBV-infected cancer cells. Here, we examined several classes of drugs for their ability to kill EBV-positive gastric cancer cells while sparing EBV-negative ones. We found that Deferoxamine and Deferasirox, drugs approved for treating iron overload diseases, can selectively kill EBV-positive gastric cancer cells grown in culture. However, when administered to immunodeficient mice, these drugs failed to significantly induce lytic EBV infection in EBV-positive gastric tumors that had been ectopically grown in the animals. ABSTRACT: Latent infection of Epstein-Barr virus (EBV) is associated with lymphoid and epithelial cell cancers, including 10% of gastric carcinomas. We previously reported that hypoxia inducible factor-1α (HIF-1α) induces EBV’s latent-to-lytic switch and identified several HIF-1α-stabilizing drugs that induce this viral reactivation. Here, we tested three classes of these drugs for preferential killing of the EBV-positive gastric cancer AGS-Akata cell line compared to its matched EBV-negative AGS control. We observed preferential killing with iron chelators [Deferoxamine (DFO); Deferasirox (DFX)] and a prolyl hydroxylase inhibitor (BAY 85-3934 (Molidustat)), but not with a neddylation inhibitor [MLN4924 (Pevonedistat)]. DFO and DFX also induced preferential killing of the EBV-positive gastric cancer AGS-BDneo and SNU-719 cell lines. Preferential killing was enhanced when low-dose DFX (10 μM) was combined with the antiviral prodrug ganciclovir. DFO and DFX induced lytic EBV reactivation in approximately 10% of SNU-719 and 20-30% of AGS-Akata and AGS-BDneo cells. However, neither DFO nor DFX significantly induced synthesis of lytic EBV proteins in xenografts grown in NSG mice from AGS-Akata cells above the level observed in control-treated mice. Therefore, these FDA-approved iron chelators are less effective than gemcitabine at promoting EBV reactivation in vivo despite their high specificity and efficiency in vitro.