Valproic Acid Enhances the Efficacy of Chemotherapy in EBV-Positive Tumors by Increasing Lytic Viral Gene Expression

Abstract

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 EBVpositive 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 EBVdriven 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.

Novel Targets for Natural Killer/T-cell Lymphoma Immunotherapy

“…However, TLR 2 triggering has been reported to induce EBV lytic protein, which is more highly immunogenic than latent protein, indicating that the TLR 2 ligand can play a role not only in stimulating immune cells but also in augmenting the immunogenicity of NKTL [56]. In addition to TLR 2 ligands, valproic acid increases the susceptibility of NKTL to T-cells because of its ability to increase EBV lytic protein expression in EBV-positive tumors [57]. Although costimulatory molecules such as CD40, OX40, and 4-1BB are attractive adjuvants for peptide vaccines against solid tumors, caution should be taken in using them for treatment of NKTL because these costimulatory molecules can also stimulate NK cells [58].…”

“…Because HDACis have been reported to induce EBV lytic proteins in EBV-positive tumors [57], the upregulation of antigen expression by these reagents would stimulate EBV-specific T-cells. In addition to their epigenetic effects, HDACi can also induce autophagy, which plays an important role in antigen processing.…”

Bortezomib and SAHA Synergistically Induce ROS-Driven Caspase-Dependent Apoptosis of Nasopharyngeal Carcinoma and Block Replication of Epstein–Barr Virus

“…Proteasome and HDAC inhibitors were also reported to induce EBV lytic cycle in different EBV-associated malignancies and lead to specific therapeutic effects against the cancer cells (11,12,23,24). Bortezomib was reported to induce EBV lytic cycle in EBV-positive Burkitt lymphoma and gastric carcinoma cells (25).…”

Host epigenetic modifications by oncogenic viruses

“…At present, five trials are investigating the use of HDAC inhibitor valproic acid (VPA) in Kaposi sarcoma, EBV-related nasopharyngeal carcinoma and non-Hodgkin's lymphoma, as well as in HIV-infected patients (http://clinicaltrials.gov/). Some circumspection is required, however, because histone deacetylase inhibitors, including valproate, may induce lytic replication, as has been shown for KSHV and EBV (Klass et al, 2005;Feng and Kenney, 2006;Lu et al, 2006). For an effective drug, it would be preferable to induce lytic replication and induce apoptosis without increasing the viral load.…”