Abstract
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 the lytic phase and antiviral valganciclovir to enhance cell death and prevent virus production. CLVA treatment has proven safe in phase-I/II trials with promising clinical responses in patients with recurrent NPC. However, a major challenge is to maximize EBV lytic reactivation by CLVA. Curcumin, a dietary spice used in Asian countries, is known for its antitumor property and therapeutic potential. Novel curcuminoids that were developed to increase efficacy and bioavailability may serve as oral CLVA adjuvants. We investigated the potential of curcumin and its analogs (curcuminoids) 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. 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 analyzed by cytotoxicity and mRNA 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. Micromolar concentration of curcuminoid EF24 enhanced the CLVA effect in all cell systems except SNU719, a naturally infected EBVaGC cell that carries a more tightly latent viral genome. These findings indicated that EF24 has potential as EBV lytic activator and may serve as an adjuvant in CLVA treatment.
Highlights
Epithelial malignancies associated with Epstein-Barr virus (EBV) infection include undifferentiated nasopharyngeal carcinoma (NPC) and a subset of gastric carcinoma (GC) [1].EBV is detected in most of NPC cases in endemic countries
We have previously reported that the Cytolytic virus activation (CLVA) drug regimen, significantly and synergistically reactivates the latent virus in NPC tumor cells into the lytic replicative phase both in vitro and in vivo and applied this strategy in a clinical Phase-I/-II trial with promising clinical responses [5,6,7]
We hypothesized that curcuminoids may act as EBV lytic induction sensitizer through their NF-κB modulating effect [10,13,14,20,21,22,23]
Summary
Epithelial malignancies associated with Epstein-Barr virus (EBV) infection include undifferentiated nasopharyngeal carcinoma (NPC) and a subset of gastric carcinoma (GC) [1]. EBV is detected in most of NPC cases in endemic countries. More than 80% of post-surgical gastric stump or remnants, the lymphoepithelioma-like (LEL) GC, and about 10% of gastric adenocarcinoma cases around the world show evidence of EBV infection called EBV associated gastric carcinoma (EBVaGC). Patients with EBVaGC had longer survival than those GC patients with no evidence of EBV [2,3]. In NPC, both hyperplastic, pre-invasive, and invasive lesions of the nasopharynx show the presence of monoclonal viral episomes [1], whereas EBV genomes persist only in fully malignant. EBVaGC lesions in the proximal stomach [2,3]. Contrary to EBVaGC, which occurs worldwide, NPC is rare in most parts of the world, but notoriously common in the Southern China, Southeast Asia, North
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