The efficacy of gene therapy treatments is hindered by molecular defense mechanisms inside eukaryotic cells that are designed to prevent the expression of foreign (e.g. viral) transgenes. For example, transgenes can be silenced by DNA methyltransferase (DNMT), an enzyme that methylates CpG motifs within promoters. Alternatively, delivery of plasmid DNA to cells has also been shown to induce the expression of inflammatory cytokines (e.g. IL-6) that repress transgene expression. In this study, we sought to increase transgene expression by inhibiting these host cell defense mechanisms with two small molecule inhibitors - caffeic acid and chlorogenic acid - that are known to inhibit DNMT and decrease inflammation. Our data show that both caffeic acid and chlorogenic acid significantly increase transgene expression in PC-3 cells by about 4-fold and 3-fold, respectively, but no significant enhancement was observed in SKBR3 or MCF-7 cells. Bisulfite assays for DNA methylation revealed that these inhibitors had no effect on promoter methylation, but an ELISA for IL-6 expression showed that the inhibitors significantly decrease IL-6 levels in PC-3 cells, with no significant effect on IL-6 expression in MCF-7 cells. Therefore, caffeic acid and chlorogenic acid may increase transgene expression in PC-3 cells by inhibiting IL-6 mediated gene silencing rather than inhibition of DNMT.