Banerjee, T. 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

NewLink Genetics Corporation, Ames, IA, USA.
Oncogene (Impact Factor: 8.46). 06/2008; 27(20):2851-7. DOI: 10.1038/sj.onc.1210939
Source: PubMed


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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Available from: Andrew L Mellor, Apr 02, 2014
    • "Other external factors could also affect brain development by interfering with the kynurenine pathway. Stress, for example , induces corticosteroid secretion which induces and activates TDO, while the diet includes compounds such as the brassinins which inhibit the kynurenine pathway (Banerjee et al., 2008). Despite the differences between enzyme inhibition and deletion models, the two approaches should reflect different clinical conditions. "
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    ABSTRACT: Glutamate receptors sensitive to N-methyl-D-aspartate (NMDA) are involved in embryonic brain development but their activity may be modulated by the kynurenine pathway of tryptophan metabolism which includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Our previous work has shown that prenatal inhibition of the pathway produces abnormalities of brain development. In the present study kynurenine and probenecid (both 100mg/kg, doses known to increase kynurenic acid levels in the brain) were administered to female Wistar rats on embryonic days E14, E16 and E18 of gestation and the litter was allowed to develop to post-natal day P60. Western blotting revealed no changes in hippocampal expression of several proteins previously found to be altered by inhibition of the kynurenine pathway including the NMDA receptor subunits GluN1, GluN2A and GluN2B, as well as doublecortin, Proliferating Cell Nuclear Antigen (PCNA), sonic hedgehog and unco-ordinated (unc)-5H1 and 5H3. Mice lacking the enzyme kynurenine-3-monoxygenase (KMO) also showed no changes in hippocampal expression of several of these proteins or the 70kDa and 100kDa variants of Disrupted in Schizophrenia-1 (DISC1). Electrical excitability of pyramidal neurons in the CA1 region of hippocampal slices was unchanged, as was paired-pulse facilitation and inhibition. Long-term potentiation was decreased in the kynurenine-treated rats and in the KMO(-/-) mice, but galantamine reversed this effect in the presence of nicotinic receptor antagonists, consistent with evidence that it can potentiate glutamate at NMDA receptors. It is concluded that interference with the kynurenine pathway in utero can have lasting effects on brain function of the offspring, implying that the kynurenine pathway is involved in the regulation of early brain development.
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    • "In the present study, galanal was found to possess more IDO1 inhibitory potency than either the most-commonly used 1-MT or other previously-published inhibitors (Table. 1) [14] [28] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43]. Since the IC50 value of inhibitor depends on the IDO1 enzyme activity in each experiment, we could not unconditionally compare the previous results. "
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    ABSTRACT: Indoleamine 2,3-dioxygenase (IDO) 1, that catalyzes the first and rate-limiting step in the degradation of L-tryptophan, has an important immunomodulatory function. The activity of IDO1 increases in various inflammatory diseases, including tumors, autoimmune diseases, and different kinds of inflammation. We evaluated the suppressive effect of plant extracts or phytochemicals on IDO1 induction and activity; sixteen kinds of plants extracts and fourteen kinds of phytochemicals were examined. As a result, the methanol extracts of Myoga flower buds, which are traditional Japanese foods, and labdane-type diterpene galanal derived from Myoga flowers significantly suppressed IDO1 activity. The Lineweaver-Burk plot analysis indicated that galanal is a competitive inhibitor. Galanal attenuated L-kynurenine formation with an IC50 value of 7.7 µM in the assay system using recombinant human IDO1, and an IC50 value of 45 nM in the cell-based assay. Further, mechanistic analysis revealed that galanal interfered with the transcriptional function of the nuclear factor-κB and the interferon-γ signaling pathway. These effects of galanal are important for immune response. Because the inhibitory effect of galanal on IDO1 activity was stronger than that of 1-methyl tryptophan, a tryptophan analog, galanal may have great potential as the novel drug for various immune-related diseases.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "Antitumor efficacy is more likely to manifest when d-1MT is used in combination with other anti-cancer treatments because blocking IDO does not incite anti-tumor immunity per se. The anti-tumor and immune enhancing effects of d-1MT treatment were also replicated by administering other compounds that inhibit IDO1- encoded IDO enzyme activity in vitro and in IDO1-transfected cells such as 5-Br-brassinin, menadione, methyl-thiohydantointryptophan , and analogs of phenylimidazole (Muller and Scherle, 2006; Banerjee et al., 2008;Kumar et al., 2008). Recently, hydroxyamidine inhibitors were also reported to suppress tryptophan catabolism and possess anti-tumor activity (Yue et al., 2009; Koblish et al., 2010;Liu et al., 2010), and TDO inhibitors may also be effective anti-tumor drugs based on a recent report that Kyn from tumor cells expressing TDO promoted tumor-induced immune privilege via AhR signaling (Opitz et al., 2011). "
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    ABSTRACT: The term "immune privilege" was coined to describe weak immunogenicity (hypo-immunity) that manifests in some transplant settings. We extended this concept to encompass hypo-immunity that manifests at local sites of inflammation relevant to clinical diseases. Here, we focus on emerging evidence that enhanced tryptophan catabolism is a key metabolic process that promotes and sustains induced immune privilege, and discuss the implications for exploiting this knowledge to improve treatments for hypo-immune and hyper-immune syndromes using strategies to manipulate tryptophan metabolism.
    Full-text · Article · May 2012 · Frontiers in Immunology
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