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A key in vivo antitumor mechanism of action of natural product-based brassinins is inhibition of indoleamine 2,3-dioxygenase

Oncogene volume 27, pages 2851–2857 (2008)Cite this article

Abstract

Agents that interfere with tumoral immune tolerance may be useful to prevent or treat cancer. Brassinin is a phytoalexin, a class of natural products derived from plants that includes the widely known compound resveratrol. Brassinin has been demonstrated to have chemopreventive activity in preclinical models but the mechanisms underlying its anticancer properties are unknown. Here, we show that brassinin and a synthetic derivative 5-bromo-brassinin (5-Br-brassinin) are bioavailable inhibitors of indoleamine 2,3-dioxygenase (IDO), a pro-toleragenic enzyme that drives immune escape in cancer. Like other known IDO inhibitors, both of these compounds combined with chemotherapy to elicit regression of autochthonous mammary gland tumors in MMTV-Neu mice. Furthermore, growth of highly aggressive melanoma isograft tumors was suppressed by single agent treatment with 5-Br-brassinin. This response to treatment was lost in athymic mice, indicating a requirement for active host T-cell immunity, and in IDO-null knockout mice, providing direct genetic evidence that IDO inhibition is essential to the antitumor mechanism of action of 5-Br-brassinin. The natural product brassinin thus provides the structural basis for a new class of compounds with in vivo anticancer activity that is mediated through the inhibition of IDO.

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Acknowledgements

AJM is the recipient of grants from the DoD Breast Cancer Research Program (BC044350), the State of Pennsylvania Department of Health (CURE/Tobacco Settlement Award), the Lance Armstrong Foundation and the Concern Foundation. GCP is the recipient of NIH R01 grants CA82222, CA100123 and CA109542. Additional support for this project was provided by grants to GCP from the Charlotte Geyer Foundation and the Lankenau Hospital Foundation.

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Author notes

  1. T Banerjee and J B DuHadaway: These authors contributed equally to this work.

Authors and Affiliations

  1. NewLink Genetics Corporation, Ames, IA, USA

    T Banerjee

  2. Lankenau Institute for Medical Research, Wynnewood, PA, USA

    J B DuHadaway, E Sutanto-Ward, G C Prendergast & A J Muller

  3. Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, USA

    P Gaspari & W P Malachowski

  4. Immunotherapy Center, Medical College of Georgia, Augusta, GA, USA

    D H Munn & A L Mellor

  5. Department of Pediatrics, Medical College of Georgia, Augusta, GA, USA

    D H Munn

  6. Department of Medicine, Medical College of Georgia, Augusta, GA, USA

    A L Mellor

  7. Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    G C Prendergast

  8. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    G C Prendergast & A J Muller

  9. Department of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    A J Muller

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  1. T Banerjee
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  2. J B DuHadaway
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Correspondence to A J Muller.

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Banerjee, T., DuHadaway, J., Gaspari, P. et al. A key in vivo antitumor mechanism of action of natural product-based brassinins is inhibition of indoleamine 2,3-dioxygenase. Oncogene 27, 2851–2857 (2008). https://doi.org/10.1038/sj.onc.1210939

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