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.

中文翻译：

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基于天然产物的油菜素的关键体内抗肿瘤作用机制是抑制吲哚胺2，3-二加氧酶。

干扰肿瘤免疫耐受的药物可能对预防或治疗癌症有用。brassinin是一种植物抗毒素，是一类来自植物的天然产物，其中包括广为人知的化合物白藜芦醇。在临床前模型中已证明了Brassinin具有化学预防活性，但其抗癌特性的潜在机制尚不清楚。在这里，我们显示，油菜素和合成衍生物5-溴-brassinin（5-Br-brassinin）是吲哚胺2，3-二加氧酶（IDO）的可生物利用的抑制剂，吲哚胺2，3-二加氧酶（IDO）是一种促耐受原的酶，可驱动癌症的免疫逃逸。像其他已知的IDO抑制剂一样，这两种化合物都与化学疗法联合使用，可引起MMTV-Neu小鼠的自发性乳腺肿瘤消退。此外，5-Br-Brassinin的单药治疗抑制了高度侵袭性黑素瘤同种异体移植瘤的生长。对治疗的这种反应在无胸腺小鼠中消失，表明需要主动宿主T细胞免疫，而在IDO-null基因敲除小鼠中，这提供了直接的遗传学证据，表明IDO抑制对于5-Br-Brassinin的抗肿瘤作用机制至关重要。因此，天然产物铜皮蛋白为通过抑制IDO介导的具有体内抗癌活性的新型化合物提供了结构基础。