Inhibition of Epstein-Barr virus reactivation in nasopharyngeal carcinoma cells by dietary sulforaphane.
Epstein-Barr virus (EBV) has been associated with several human malignancies including nasopharyngeal carcinoma (NPC). Reactivation of latent EBV has been considered to contribute to the carcinogenesis of NPC. Blocking the EBV lytic cycle has been shown effective in the treatment of EBV-associated diseases. We have searched for natural dietary compounds inhibiting EBV reactivation in NPC cells. Among them, sulforaphane (SFN) was found to be effective in the inhibition of EBV reactivation in latent EBV-positive NPC cells, NA and HA. SFN is a histone deacetylase (HDAC) inhibitor and has been recognized as an antioxidant and antitumor compound for chemoprevention. However, its antiviral effect is less well elucidated. In this study, after determination of the cytotoxicity of SFN on various epithelial cells, we showed that SFN treatment inhibits EBV reactivation, rather than induction, by detection of EBV lytic gene expression in EBV-positive NPC cells. We also determined that the number of cells supporting the EBV lytic cycle is decreased using immunofluorescence and flow cytometric analysis. Moreover, we have found that this inhibitory effect decreases virus production. To elucidate the inhibitory mechanism of SFN on the EBV lytic cycle, luciferase reporter assays were carried out on the Zta and Rta promoters. The results show that SFN inhibits transactivation activity of the EBV immediate-early gene Rta but not Zta. Together, our results suggest that SFN has the capability to inhibit EBV lytic cycle and the potential to be taken as a dietary compound for prevention of EBV reactivation.
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
Chung-Chun
CC
Wu
Hsin-Ying
HY
Chuang
Chao-Yi
CY
Lin
Yen-Ju
YJ
Chen
Wan-Hua
WH
Tsai
Chih-Yeu
CY
Fang
Sheng-Yen
SY
Huang
Fu-Yang
FY
Chuang
Su-Fang
SF
Lin
Yao
Y
Chang
Jen-Yang
JY
Chen
D000998:Antiviral Agents / Q000494:pharmacology; D002277:Carcinoma; D019587:Dietary Supplements; D004847:Epithelial Cells / Q000187:drug effects / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy / Q000517:prevention & control / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D017781:Genes, Immediate-Early; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D017879:Isothiocyanates / Q000494:pharmacology*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000821:virology*; D011401:Promoter Regions, Genetic; D013454:Sulfoxides; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014775:Virus Activation / Q000187:drug effects
D000998:Antiviral Agents; C068382:BRLF1 protein, Human herpesvirus 4; C063676:BZLF1 protein, Herpesvirus 4, Human; D056572:Histone Deacetylase Inhibitors; D017874:Immediate-Early Proteins; D017879:Isothiocyanates; D013454:Sulfoxides; D015534:Trans-Activators; C016766:sulforaphane