Abstract
The histone deacetylase inhibitor FK228 has previously been shown to enhance adenoviral transgene expression when cells are pre-incubated with the drug. Upregulation of the coxsackie adenovirus receptor (CAR), leading to increased viral transduction, has been proposed as the main mechanism. In the present study, we found that the highest increase in transgene expression was achieved when non-toxic concentrations of FK228 were added immediately after transduction, demonstrating that the main effect by which FK228 enhances transgene expression is transduction-independent. FK228 had positive effects both on Ad5 and Ad5/f35 vectors with a variety of transgenes and promoters, indicating that FK228 works mainly by increasing transgene expression at the transcriptional level. In some cases, the effects were dramatic, as demonstrated by an increase in CD40L expression by FK228 from 0.3% to 62% when the murine prostate cancer cell line TRAMP-C2 was transduced with Ad[CD40L]. One unexpected finding was that FK228 decreased the transgene expression of an adenoviral vector with the prostate cell-specific PPT promoter in the human prostate adenocarcinoma cell lines LNCaP and PC-346C. This is probably a consequence of alteration of the adenocarcinoma cell lines towards a neuroendocrine differentiation after FK228 treatment. The observations in this study indicate that FK228 enhances adenoviral therapy by a transduction-independent mechanism. Furthermore, since histone deacetylase inhibitors may affect the differentiation of cells, it is important to keep in mind that the activity and specificity of tissue- and tumor-specific promoters may also be affected.
Highlights
Viral vectors based on human adenovirus serotype 5 (Ad5) are the most commonly used vectors for gene therapy and they are frequently used for vaccination
Of further interest, when the prostate cancer cell lines LNCaP and PC346-C were transduced with the neuroendocrineselective Ad[chromogranin A (CgA)-LUC] vector and treated with FK228 or valproic acid (VPA), we found that transgene expression was increased
Histone deacetylase inhibitors (HDACi) have been shown to increase the effect of adenoviralmediated gene therapy the mechanisms are not fully understood [13,14,28]
Summary
Viral vectors based on human adenovirus serotype 5 (Ad5) are the most commonly used vectors for gene therapy and they are frequently used for vaccination. In cancer gene therapy their effect can be limited due to that malignant cells often have low expression of the coxsackie adenovirus receptor (CAR), which is the primary receptor for Ad5 [1]. Different means to increase CAR expression on target cells would presumably lead to enhanced adenoviral gene therapy efficacy. FK228 has been shown to enhance the effect of adenoviral-mediated therapy [13,14]. The mechanisms for this enhancement are not fully understood but upregulation of CAR has been suggested as one possibility [7,15,16,17,18]
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