1. ¹NewLink Genetics Corporation, Ames, IA, USA
2. ²Lankenau Institute for Medical Research, Wynnewood, PA, USA
3. ³Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, USA
4. ⁴Immunotherapy Center, Medical College of Georgia, Augusta, GA, USA
5. ⁵Department of Pediatrics, Medical College of Georgia, Augusta, GA, USA
6. ⁶Department of Medicine, Medical College of Georgia, Augusta, GA, USA
7. ⁷Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA
8. ⁸Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
9. ⁹Department of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA

Correspondence: Dr A Muller, Tumor Immunology and Molecular Genetics, Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA. E-mail: mullera@mlhs.org

¹⁰These authors contributed equally to this work.

Received 19 June 2007; Revised 14 September 2007; Accepted 11 October 2007; Published online 19 November 2007.

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.