Curcumin analogs as putative Epstein-Barr virus lytic activators for adjuvant treatment in carcinomas

摘要: Introduction: Epstein-Barr virus (EBV) persists in nasopharyngeal (NPC) and gastric carcinomas (EBVaGC) in a tightly latent form. Cytolytic virus activation (CLVA) therapy employs gemcitabine and valproic acid (GCb+ VPA) to reactivate latent EBV into lytic phase and antiviral valganciclovir to enhance cell death and prevent virus production. CLVA has proven safe with promising clinical responses in patients with recurrent NPC. However a major challenge is to maximize EBV lytic reactivation by CLVA. Curcumin, dietary spice used in Asian countries is known for its antitumor property and therapeutic potential. Novel curcuminoids which were developed to increase efficacy and bioavailability may serve as oral CLVA adjuvant.Methods: We investigated the potential of curcumin and its analogs to trigger the EBV lytic cycle in EBVaGC and NPC cells. EBV-reactivating effects were measured by immunoblot and immunofluorescence using monoclonal antibodies specific for EBV lytic proteins.Results: Two of the hit compounds (41, EF24) with high lytic inducing activity were further studied for their synergistic or antagonistic effects when combined with GCb+ VPA and analysed by cytotoxicity and RNA profiling assays to measure the EBV reactivation. Curcuminoid as a single agent significantly induced EBV reactivation in recombinant GC and NPC lines. The drug effects were dose-and time-dependent.Conclusions: Micromolar concentration of curcuminoid EF24enhanced the CLVA effect in all cell systems except SNU719, a naturally infected EBVaGC cells which carry a more tightly latent viral genome. These findings indicated that EF24 has potential …