An HDAC inhibitor enhances the antitumor activity of a CMV promoter-driven DNA vaccine

• Published in: Cancer gene therapy Vol. 17; no. 3; pp. 203 - 211
• Main Authors: Lai, M-D, Chen, C-S, Yang, C-R, Yuan, S-Y, Tsai, J-J, Tu, C-F, Wang, C-C, Yen, M-C, Lin, C-C
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2010; Nature Publishing Group
• Subjects: Animals; Antigens; Antitumor activity; Biomedical and Life Sciences; Biomedicine; Bladder cancer; Cell Line, Tumor; Chromatin; Cytomegalovirus; Cytomegalovirus - genetics; Cytomegaloviruses; Dendritic Cells - immunology; Dendritic Cells - metabolism; Deoxyribonucleic acid; DNA; DNA vaccines; ErbB-2 protein; Gene Expression; Gene Expression - drug effects; Gene Expression - genetics; Gene Therapy; Genetic aspects; Health aspects; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Immune response; Immune response (cell-mediated); Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - therapy; NIH 3T3 Cells; original-article; Phenylbutyrates - pharmacology; Phenylbutyrates - therapeutic use; Physiological aspects; Plasmids; Promoters (Genetics); Prostatic Neoplasms - metabolism; Prostatic Neoplasms - therapy; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Tumors; Vaccines; Vaccines, DNA - genetics; Vaccines, DNA - therapeutic use; Taiwan; DNA vaccine; cytomegalovirus promoter; histone deacetylase inhibitor; tumor
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/cgt.2009.65

The cytomegalovirus (CMV) promoter is considered to be one of the strongest promoters for driving the in vivo expression of genes encoded by DNA vaccines. However, the efficacy of DNA vaccines has so far been disappointing (particularly in humans), and this might be explained in part by histone deacetylase (HDAC)-mediated chromatin condensation. Hence, we sought to investigate whether increasing the expression of DNA vaccine antigens with the HDAC inhibitor OSU-HDAC42 would enhance the efficacy of DNA vaccines in vivo . A luciferase assay was used to determine the effects of OSU-HDAC42 on CMV promoter-driven DNA plasmids in vitro and in vivo . Three HDAC inhibitors were able to activate expression from the CMV promoter in NIH3T3 cells and MBT-2 bladder cancer cells. The expression of luciferase was significantly enhanced by co-administration of pCMV-luciferase and OSU-HDAC42 in mice. To explore whether OSU-HDAC42 could enhance the specific antitumor activity of a neu DNA vaccine driven by the CMV promoter, we evaluated therapeutic effects and immune responses in a mouse tumor natively overexpressing HER2/neu. Mice receiving OSU-HDAC42 in combination with the CMV-promoter neu DNA vaccine exhibited stronger antitumor effects than mice given the DNA vaccine only. In addition, a correlation between the antitumor effects and the specific cellular immune responses was observed in the mice receiving the DNA vaccine and OSU-HDAC42.