Abstract
BackgroundThe presence of CAR in diverse tumor types is heterogeneous with implications in tumor transduction efficiency in the context of adenoviral mediated cancer gene therapy. Preliminary studies suggest that CAR transcriptional regulation is modulated through histone acetylation and not through promoter methylation. Furthermore, it has been documented that the pharmacological induction of CAR using histone deacetylase inhibitor (iHDAC) compounds is a viable strategy to enhance adenoviral mediated gene delivery to cancer cells in vitro. The incorporation of HDAC drugs into the overall scheme in adenoviral based cancer gene therapy clinical trials seems rational. However, reports using compounds with iHDAC properties utilized routinely in the clinic are pending. Valproic acid, a short chained fatty acid extensively used in the clinic for the treatment of epilepsy and bipolar disorder has been recently described as an effective HDAC inhibitor at therapeutic concentrations.MethodsWe studied the effect of valproic acid on histone H3 and H4 acetylation, CAR mRNA upregulation was studied using semiquantitative PCR and adenoviral transduction on HeLa cervical cancer cells, on MCF-7 breast cancer cells, on T24 transitional cell carcinoma of the bladder cells. CAR mRNA was studied using semiquantitative PCR on tumor tissue extracted from patients diagnosed with cervical cancer treated with valproic acid.ResultsCAR upregulation through HDAC inhibition was observed in the three cancer cell lines with enhancement of adenoviral transduction. CAR upregulation was also observed in tumor samples obtained from patients with cervical cancer treated with therapeutic doses of valproic acid. These results support the addition of the HDAC inhibitor valproic acid to adenoviral mediated cancer gene therapy clinical trials to enhance adenoviral mediated gene delivery to the tumor cells.
Highlights
The presence of coxsackie adenovirus receptor (CAR) in diverse tumor types is heterogeneous with implications in tumor transduction efficiency in the context of adenoviral mediated cancer gene therapy
Valproic acid (VPA), a short chained fatty acid extensively used in the clinic to treat epilepsy and bipolar disorder has been described as an effective Histone deacetilases (HDAC) inhibitor [24,25,26,27]
We studied the effect of VPA on CAR expression on HeLa cervical cancer cells, on MCF-7 breast cancer cells, on T24 transitional cell carcinoma of the bladder cells and on tumor biopsies from patients with cervical cancer treated with VPA
Summary
The presence of CAR in diverse tumor types is heterogeneous with implications in tumor transduction efficiency in the context of adenoviral mediated cancer gene therapy. Genetic Vaccines and Therapy 2007, 5:10 http://www.gvt-journal.com/content/5/1/10 duction efficiency in the context of adenovirus based cancer gene therapy [7,8,9,10] In this regard, initial findings suggest that CAR transcriptional regulation is modulated through local remodeling of the chromatin structure, mainly through histone acetylation and not through promoter methylation even though the putative promoter contains several CpG di-nucleotides [11]. Various groups have corroborated this finding utilizing various histone deacetylace inhibitors (iHDAC) to induce CAR gene expression, increase CAR presence on the surface of the tumor cells and enhance adenoviral transduction [12,13,14]. We studied the effect of VPA on CAR expression on HeLa cervical cancer cells, on MCF-7 breast cancer cells, on T24 transitional cell carcinoma of the bladder cells and on tumor biopsies from patients with cervical cancer treated with VPA
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