Valproic Acid, a Histone Deacetylase Inhibitor, Is an Antagonist for Oncolytic Adenoviral Gene Therapy

Naseruddin Höti, Wasim Chowdhury, Jer Tsong Hsieh, Markus D. Sachs, Shawn E. Lupold, Ronald Rodriguez

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Oncolytic adenoviruses preferentially replicate in and lyse tumor cells. However, their application to cancer gene therapy has been complicated by the low levels of coxsackie and adenovirus receptor (CAR) expressed in many solid tumors. Histone deacetylase inhibitors (HDACIs) significantly up-regulate CAR expression in tumor cells and have additional antineoplastic activities. Therefore, there is a clear rationale for the combination of HDACIs and oncolytic adenoviral gene therapy. We present evidence that HDACI treatment significantly inhibits adenoviral replication, viral burst, and tumor cell kill. Valproic acid (VPA), a well-established HDACI, inhibits adenoviral replication late in the viral life cycle. We hypothesized that VPA induction of the cell-cycle-regulating protein p21WAF1/CIP1 may be partly responsible for this activity. We demonstrate that p21WAF1/CIP1 expression alone limits viral replication and decreases viral titers in different cancer cell models. We also demonstrate that VPA and replicating adenovirus mutually inhibit each other's ability to kill cells, independent of p21WAF1/CIP1 expression. These results not only identify the importance of p21WAF1/CIP1 in the biology of adenoviral replication, but also suggest that oncolytic adenoviral gene therapy will be inhibited rather than enhanced by VPA (HDACI) treatment.

Original languageEnglish (US)
Pages (from-to)768-778
Number of pages11
JournalMolecular Therapy
Volume14
Issue number6
DOIs
StatePublished - Dec 1 2006

Keywords

  • E1A
  • VPA
  • adenovirus
  • fiber-IRES-GFP
  • p21

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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