HDAC inhibitor valproic acid enhances tumor cell kill in adenovirus-HSVtk mediated suicide gene therapy in HNSCC xenograft mouse model

Vishal Kothari, Ganesh Joshi, Srikanth Nama, Kumaravel Somasundaram, Rita Mulherkar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Safety, efficacy and enhanced transgene expression are the primary concerns while using any vector for gene therapy. One of the widely used vectors in clinical trials is adenovirus which provides a safe way to deliver the therapeutic gene. However, adenovirus has poor transduction efficiency in vivo since most tumor cells express low coxsackie and adenovirus receptors. Similarly transgene expression remains low, possibly because of the chromatization of adenoviral genome upon infection in eukaryotic cells, an effect mediated by histone deacetylases (HDACs). Using a recombinant adenovirus (Ad-HSVtk) carrying the herpes simplex thymidine kinase (HSVtk) and GFP genes we demonstrate that HDAC inhibitor valproic acid can bring about an increase in CAR expression on host cells and thereby enhanced Ad-HSVtk infectivity. It also resulted in an increase in transgene (HSVtk and GFP) expression. This, in turn, resulted in increased cell kill of HNSCC cells, following ganciclovir treatment in vitro as well as in vivo in a xenograft nude mouse model.

Original languageEnglish (US)
Pages (from-to)733-742
Number of pages10
JournalInternational Journal of Cancer
Volume126
Issue number3
DOIs
StatePublished - Feb 1 2010

Keywords

  • Adenoviral vector
  • Cancer gene therapy
  • HDAC inhibitors
  • Prodrug activation
  • Valproic acid

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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