Abstract
Epstein-Barr virus (EBV) has widely infected more than 90% of human populations. Currently, there is no efficient way to remove the virus because the EBV carriers are usually in a latent stage that allows them to escape the immune system and common antiviral drugs. In the effort to develop an efficient strategy for the removal of the EBV virus, we have shown that betulinic acid (BA) slightly suppresses EBV replication through SOD2 suppression with subsequent reactive oxygen species (ROS) generation and DNA damage in EBV-transformed LCL (lymphoblastoid cell line) cells. Chidamide (CDM, CS055), a novel histone deacetylase inhibitor (HDACi), could significantly switch EBV from the latent stage to the lytic stage with increased gene expression of BZLF1 and BMRF1, but has a small effect on EBV replication due to the suppression effect of CDM-mediated ROS generation. Interestingly, a combination of BA and CDM synergistically inhibits EBV replication with ROS over-generation and subsequent DNA damage and apoptosis. Overexpression of SOD2 diminishes this effect, while SOD2 knockdown mimics this effect. An in vivo xenograft tumor development study with the tail vein injection of EBV-transformed LCL cells in nude mice proves that the combination of BA and CDM synergistically increases superoxide anion release in tumor tissues and suppresses EBV replication and tumor growth, and significantly prolongs mouse survival. We conclude that the combination of BA and CDM could be an efficient strategy for clinical EBV removal.
Highlights
In the effort to develop an efficient strategy for the removal of the Epstein-Barr virus (EBV) virus, we have shown that betulinic acid (BA) slightly suppresses EBV replication through SOD2 suppression with subsequent reactive oxygen species (ROS) generation and DNA damage in EBV-transformed LCL cells
Our results showed that BA-mediated SOD2 suppression, including mRNA level and protein level, was completely normalized by CREB
These results indicate that BA-mediated EBV inhibition is due to BA-induced SOD2 suppression and the subsequent oxidative stress
Summary
Epstein-Barr virus (EBV) is a human γ-herpesvirus that infects more than 90% of human populations. Current anti-herpes virus drugs, including nucleoside analogs ganciclovir (GCV) and acyclovir, are usually inefficient in removing the EBV virus from patients, as EBV maintains a latent stage and lytic-phase proteins are required to convert these pro-drugs to active antiviral drugs [3]. Development of an efficient anti-EBV removal strategy is still a challenge. BA can inhibit the hepatitis B virus through SOD2 suppression with subsequent oxidative stress [7], indicating that BA may be a potential candidate for development of anti-EBV drugs. Some histone deacetylase inhibitors (HDACi) [8], such as MS275 [9], can be a potent activator in switching EBV from the latent to lytic stage, and subsequently sensitizes lymphoma cells to nucleoside antiviral agents [3]. CDM (CS055) can induce significant cell-cycle arrest, resulting in the inhibition of cell proliferation and apoptosis in leukemia cells [11], while there is no report about the effect of CDM (CS055) on EBV
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