1. ¹Department of Surgery, The University of Chicago, Chicago, IL, USA
2. ²Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA
3. ³Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL, USA
4. ⁴Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA

Correspondence: Professor RR Weichselbaum, Department of Radiation and Cellular Oncology, The University of Chicago, 5758 S. Maryland Avenue, Chicago, IL 60637, USA. E-mail: rrw@radonc.uchicago.edu

⁵These authors contributed equally to this study.

Received 26 July 2007; Revised 21 September 2007; Accepted 3 October 2007; Published online 21 December 2007.

Abstract

We report the anticarcinogenic, anti-aging polyphenol resveratrol activates the radio- and chemo-inducible cancer gene therapy vector Ad.Egr.TNF, a replication-deficient adenovirus that expresses human tumor necrosis factor (TNF-) under control of the Egr-1 promoter. Like ionizing radiation or chemotherapeutic agents previously shown to activate Ad.Egr.TNF, resveratrol also induces Egr-1 expression from its chromosomal locus with a possible role for Egr-1 promoter CC(A+T)richGG sequences in the expression of TNF-. Resveratrol induction of TNF- in Ad.Egr.TNF-infected tumor xenografts demonstrated antitumor response in human and rat tumor models comparable to that of radio- or chemotherapy-induced TNF-. Although sirtuins are known targets of resveratrol, in vitro inhibition of SIRT1 activity did not abrogate resveratrol induction of Egr-1 expression. This suggests that SIRT1 is not essential to mediate resveratrol induction of Egr-1. Nevertheless, control of transgene expression via resveratrol activation of Egr-1 may extend use of Ad.Egr.TNF to patients intolerant of radiation or cytotoxic therapy and offer a novel tool for development of other inducible gene therapies.