Combination of betulinic acid and chidamide synergistically inhibits Epstein-Barr virus replication through over-generation of reactive oxygen species
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Haibing Yu1,*, Hongyu Zhang2,*, Zhigang Chu3, Qiongfang Ruan3, Xueru Chen2, Danli Kong1, Xiaodong Huang3, Huawen Li1, Huanwen Tang1, Hongjin Wu4, Yifei Wang5, Weiguo Xie3, Yuanling Ding1 and Paul Yao1,2,3
1School of Public Health, Guangdong Medical University, Dongguan 523808, PR China
2Department of Hematology, Peking University Shenzhen Hospital, Shenzhen 518036, PR China
3Institute of Burns, Tongren Hospital of Wuhan University, Wuhan 430060, PR China
4Beijing Haidian Hospital, Haidian Section of Peking University 3rd Hospital, Beijing 100080, PR China
5Guangzhou Biomedical Research and Development Center, Jinan University, Guangzhou 510632, PR China
*These authors have contributed equally to this work
Paul Yao, email: firstname.lastname@example.org
Yuanling Ding, email: email@example.com
Weiguo Xie, email: firstname.lastname@example.org
Keywords: betulinic acid, chidamide, Epstein-Barr virus, reactive oxygen species, histone deacetylase inhibitor
Received: March 24, 2017 Accepted: May 23, 2017 Published: June 27, 2017
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.
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