Abstract
Background Epstein-Barr virus (EBV) is causally involved in various lymphoid and non-lymphoid cancers, including nasopharyngeal (NPC) and stomach carcinomas (EBVaGC). NPC is endemic in south east Asia, including Indonesia. EBVaGC accounts for about 10% of GC worldwide. We recently initiated efforts to target EBV inside tumour cells by cytolytic virus activation therapy (CLVA), currently being validated in a phase 1/2 trial. We aim to develop oral drugs to improve CLVA treatment availability for low-income countries. Curcumin (diferuloylmethane) from Curcuma longa is used as spice in Asian countries without any toxic effects and has anti-cancer activity. Several curcumin analogues (curcuminoids), developed to increase efficacy and bioavailability, are currently being tested in clinical studies. Curcuminoids affect multiple pathways, including inhibition of COX2 and NF-kB and have potential as oral CLVA regimens for EBV-positive carcinoma. Methods We investigated EBV-reactivating effects of curcuminoids on EBV-positive NPC (C666.1) and EBVaGC cell lines (SNU179 and AGS-BX1). EBV-negative GC (AGS) line was used as a negative control. Standard CLVA, SAHA, and bortezomib were used as positive controls. EBV lytic (Zebra, EA-D) activity was measured by semi-quantitative immunoblot, FACS and indirect immunofluorescence. Effects on cell viability were measured by MTT assay. Findings Curcumin induced EBV lytic activity in AGS-BX1 cells but had marginal effect on natural EBV lines (C666.1,SNU179). However, several curcumin analogues induced EBV reactivation in all three EBV-positive cell lines in a dose- and time-dependent manner. MTT assay showed curcuminoids to be more toxic to EBVaGC cells than to C666.1 cells. Noteworthy curcuminoids showed synergistic effects with current lytic induction agents. Interpretation Curcumin analogues serve as non-toxic drugs to reactivate EBV from latently infected NPC and GC cells, but seem to reactivate EBV differently in NPC versus GC. Curcuminoids at pharmacologically relevant concentrations may promote cytolysis of EBV-positive carcinoma when combined with CLVA drugs. The molecular mechanisms of EBV lytic cycle induction by curcuminoids will be studied to gain further insights in EBV reactivation from latency in different carcinoma models.
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