Valproic acid enhances the efficacy of chemotherapy in EBV-positive tumors by increasing lytic viral gene expression.
EBV infection in tumor cells is generally restricted to the latent forms of viral infection. Switching the latent form of viral infection into the lytic form may induce tumor cell death. We have previously reported that certain chemotherapy agents can increase the amount of lytic viral gene expression in EBV-positive tumor cells. In this report, we have explored the potential utility of valproic acid (VPA), an anti-seizure drug that also has strong histone deacetylase inhibitory activity, for activating lytic viral gene expression in EBV-positive tumors. Although VPA treatment alone induced only a modest increase in the level of lytic viral gene expression, it strongly enhanced the ability of chemotherapeutic agents to induce lytic EBV gene expression in EBV-positive epithelial and lymphoid cells in vitro. Furthermore, VPA enhanced cell killing in vitro by chemotherapeutic agents in lymphoblastoid cells and gastric cells (AGS) containing wild-type EBV. In contrast, VPA did not enhance the cytotoxicity of chemotherapy in lymphoblastoid cells containing a lytic-defective (BZLF1-knockout) form of EBV or in EBV-negative AGS cells. Finally, we found that the combination of VPA and chemotherapy was significantly more effective in inhibiting EBV-driven lymphoproliferative disease in severe combined immunodeficient mice than chemotherapy alone. These results suggest that VPA could potentiate the efficacy of chemotherapy for EBV-positive tumors in patients.
Feng
Wen-Hai
WH
Department of Medicine and Microbiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Kenney
Shannon C
SC
D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000188:drug therapy; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D017930:Genes, Reporter; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000302:isolation & purification*; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000821:virology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000821:virology*; D014183:Transplantation, Heterologous; D014635:Valproic Acid / Q000627:therapeutic use*
D014635:Valproic Acid; D008156:Luciferases