Resveratrol is an effective inducer of CArG-driven TNF-α gene therapy

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 a (TNF-alpha) 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-alpha. Resveratrol induction of TNF-alpha 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-alpha. 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.