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

Cancer Gene Therapy volume 15, pages 133–139 (2008)Cite this article

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 α (TNF-α) 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-α. Resveratrol induction of TNF-α 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-α. 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.

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Acknowledgements

We thank Dr Rory Curtis and Dr Julie Huber of Elixir Pharmaceuticals for providing the SIRT1 inhibitor compounds Ex-527, Ex-243 and Ex-242 and Dr Carl Maki (University of Chicago, IL) for helpful discussions. These studies were supported by NIH grant CA111423, a gift from the Foglia Family and funds from the Ludwig Foundation for Cancer Research to RRW. SJK was a Cancer Research Foundation Fletcher Scholar and a Leukemia & Lymphoma Society Scholar.

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Author notes

  1. K A Bickenbach, J Veerapong and M Y Shao: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Surgery, The University of Chicago, Chicago, IL, USA

    K A Bickenbach, J Veerapong, M Y Shao & M C Posner

  2. Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA

    H J Mauceri & R R Weichselbaum

  3. Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL, USA

    S J Kron

  4. Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA

    S J Kron & R R Weichselbaum

Authors
  1. K A Bickenbach
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  2. J Veerapong
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  3. M Y Shao
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  4. H J Mauceri
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  5. M C Posner
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  6. S J Kron
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  7. R R Weichselbaum
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Corresponding author

Correspondence to R R Weichselbaum.

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Disclosures of potential conflict of interest

RRW is a co-inventor of Ad.Egr.TNF (TNFerade Biologic), a gene therapy under development by GenVec. Dr Weichselbaum has received research funds from, is a paid consultant for and owns equity in GenVec.

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Bickenbach, K., Veerapong, J., Shao, M. et al. Resveratrol is an effective inducer of CArG-driven TNF-α gene therapy. Cancer Gene Ther 15, 133–139 (2008). https://doi.org/10.1038/sj.cgt.7701103

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  • DOI: https://doi.org/10.1038/sj.cgt.7701103

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