HDAC inhibitor valproic acid upregulates CAR in vitro and in vivo
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BioMed Central
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HDAC inhibitor valproic acid upregulates CAR in vitro and in vivo Blanca Segura-Pacheco†, Berenice Avalos†, Edgar Rangel, Dora Velazquez and Gustavo Cabrera* Address: Vectorology and Gene Therapy Laboratory, National Cancer Institute, Av. San Fernando No 22, Del. Tlalpan, CP 14080, Mexico City, Mexico Email: Blanca Segura-Pacheco - [email protected]; Berenice Avalos - [email protected]; Edgar Rangel - [email protected]; Dora Velazquez - [email protected]; Gustavo Cabrera* - [email protected] * Corresponding author †Equal contributors
Published: 24 September 2007 Genetic Vaccines and Therapy 2007, 5:10
doi:10.1186/1479-0556-5-10
Received: 4 May 2007 Accepted: 24 September 2007
This article is available from: http://www.gvt-journal.com/content/5/1/10 © 2007 Segura-Pacheco et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: 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. 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. Methods: We 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. Results: CAR 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 tumo
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