title: Resveratrol is an effective inducer of CArG-driven TNF-alpha gene therapy.
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 alpha (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.
authors.affiliation: Department of Surgery, The University of Chicago, Chicago, IL, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Bickenbach
authors.forename: J
authors.initials: J
authors.lastname: Veerapong
authors.forename: M Y
authors.initials: MY
authors.lastname: Shao
authors.forename: H J
authors.initials: HJ
authors.lastname: Mauceri
authors.forename: M C
authors.initials: MC
authors.lastname: Posner
authors.forename: S J
authors.initials: SJ
authors.lastname: Kron
authors.forename: R R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D000077185:Resveratrol; D037761:Sirtuins / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D051766:Early Growth Response Protein 1; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D037761:Sirtuins; D000077185:Resveratrol