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

NewLink Genetics Corporation, Ames, IA, USA.
Oncogene (Impact Factor: 8.56). 06/2008; 27(20):2851-7. DOI: 10.1038/sj.onc.1210939
Source: PubMed

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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Available from: Andrew L Mellor, Apr 02, 2014
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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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    • "Until recently, the best known IDO inhibitors [15] displayed affinities in the micromolar range and comprised mainly Trp derivatives such as 1-methyl-L-tryptophan (1MT) [16] (K i w 34 mM) and b-carbolines [17]. In 2006, potent nanomolar inhibitors were isolated from marine invertebrate extracts [18] [19] At the same time, new brassinin-based IDO inhibitors were published [20] [21], the best having a K i of 12 mM. In 2008, two new classes of compounds were reported based on the earlier discovery of the marine invertebrate inhibitors. "
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    • "curcumin and epigallocatechin gallate) are in or are close to clinical trials of their chemoprevention for various cancers (Fan et al., 2006; Thomasset et al., 2007). Chinese cabbage, one of the most popular crucifers consumed worldwide , has significant bioactivity against tumorigenesis and tumour growth via the action of constituent multifunctional brassinin derivatives (Banerjee et al., 2008). Breast cancer is the most frequent tumour, with an alarming year-by-year increase in incidence, and is one of the main causes of death by cancer in women. "
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