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The HDAC Inhibitor FK228 Enhances Adenoviral Transgene Expression by a Transduction-Independent Mechanism but Does Not Increase Adenovirus Replication
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2011 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 6, no 2, e14700- p.Article in journal (Refereed) Published
Abstract [en]

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) 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 the transgene expression of an adenoviral vector with the prostate-specific PPT promoter decreased in the human prostate cancer cell line LNCaP when FK228 was administered. This is probably a consequence of phenotypic alteration of LNCaP towards a neuroendocrine phenotype 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 alter the phenotype of cells, it is important to keep in mind that the activity and specificity of tissue- and tumor-specific promoters may also be affected.

Place, publisher, year, edition, pages
2011. Vol. 6, no 2, e14700- p.
Keyword [en]
FK228, depsipeptide, HDAC inhibitor, adenovirus, CD40 ligand, prostate-specific promoter
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
URN: urn:nbn:se:uu:diva-114381DOI: 10.1371/journal.pone.0014700ISI: 000287482300006OAI: oai:DiVA.org:uu-114381DiVA: diva2:293864
Available from: 2010-02-15 Created: 2010-02-15 Last updated: 2012-06-07Bibliographically approved
In thesis
1. Adenovirus-mediated Gene Therapy of Prostate Cancer
Open this publication in new window or tab >>Adenovirus-mediated Gene Therapy of Prostate Cancer
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adenovirus-mediated gene therapy is a potential complement to standard cancer treatments. Advantages are that vectors can be used to target tumors and that replicating viruses lead to increased therapeutic dosage.

In this thesis, an oncolytic serotype 5 adenovirus (Ad5), Ad[i/PPT-E1A, E3], was developed where viral replication is controlled by the insulator-shielded (i) prostate-specific PPT promoter. The adenoviral E3 region was inserted for its immune regulatory and lysis functions. Ad[i/PPT-E1A, E3] had improved cytotoxic abilities both in vitro and in a prostate cancer xenograft mouse model compared to a virus lacking the E3 region. To further improve adenoviral vectors, the histone deacetylase inhibitor (HDACi) FK228 was studied. FK228 has been proposed to enhance the effect of adenoviral therapy by upregulation of CAR, the primary receptor for Ad5 infection. In the present study, we observed that FK228 promotes transgene expression even better when administered after viral transduction, indicating a post-transductional enhancement of transgene expression. Another interesting finding was that FK228 reduced transgene expression from the PPT promoter in the prostate cancer cell line LNCaP. This is explained by the fact that different HDACi have the ability to provoke a neuroendocrine phenotype of LNCaP.

A potential drawback with adenoviral gene therapy is the rapid clearance of the virus from the circulation. Viral particles have been coated with polyethylene glycol (PEG) to evade immune recognition, a strategy that works well in mouse models. However, less is known about the effects of adenoviral PEGylation in human blood. We have studied cell interactions and immune responses to PEGylated and uncoated Ad5 vectors in human whole blood using a blood loop model with constant blood flow. Limited effects of PEGylation were observed in human blood, which were associated with the neutralizing ability of the donor blood. An important finding that donors with high neutralizing ability in whole blood do not necessarily have neutralizing antibodies against the virus strongly implies that neutralization should be measured in whole blood.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 524
Keyword
adenovirus, adenoviral vector, oncolytic virus, gene therapy, prostate cancer, PEGylation, HDAC inhibitor, whole blood model, whole blood neutralization assay
National Category
Medical and Health Sciences
Research subject
Clinical Immunology; Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-114132 (URN)978-91-554-7726-4 (ISBN)
Public defence
2010-04-01, Rudbecksalen, Rudbecklab, Dag Hammarskjöldsväg 20, Uppsala, 09:15 (English)
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Available from: 2010-03-08 Created: 2010-02-10 Last updated: 2011-03-07Bibliographically approved

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Danielsson, Angelika

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