Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio.
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio.
Carcinogenesis. 2018 Jan 12;39(1):36-46. doi: 10.1093/carcin/bgx115.
Celastrol is an anti-inflammatory natural triterpenoid, isolated from the herb Tripterygium wilfordii or thunder god vine. Here, we define mechanisms mediating anti-inflammatory activity of celastrol and demonstrate efficacy of a dietary celastrol supplement for chemoprevention of inflammation-driven carcinogenesis in mice. Dietary celastrol (31.25 ppm in rodent diet from 8 weeks to 25 weeks of age) is well tolerated and protects against LPS-induced acute inflammation in C57BL/6 mice, potently suppressing LPS-induction of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, Interleukin (IL)-6 and IL-1β. To test whether dietary celastrol suppresses inflammation-driven colorectal cancer (CRC), we employed a unique model of spontaneous, inflammation-driven CRC in mice harboring a germ line deletion of the p27Kip1 gene and a T cell-specific deletion of Smad4 gene (Smad4co/co;Lck-crep27Kip1-/-or DKO), which develop severe intestinal inflammation and carcinogenesis as early as 3 months of age. Exposure of DKO mice to daily dietary celastrol (12.5 ppm in diet) from 6 weeks of age significantly suppressed development of colitis-associated CRC (CAC). Celastrol chemoprevention of CAC in this new model of intestinal neoplasia was associated with significant suppression of iNOS at 4 months of age, and iNOS, COX-2 and NFκB at 6 months of age, with significant reduction in inflammatory cytokines, IL-6 and IL-1β. Chemoprevetion of CAC by dietary celastrol was further confirmed in the model of azoxymethane (AOM) plus dextran sodium sulfate (DSS)-induced carcinogenesis in C57BL/6 mice. These data suggest the potential for celastrol as a safe and effective dietary supplement in the chemoprevention of CAC in humans.
雷公藤红素是一种抗炎天然三萜，从雷公藤或雷公藤中分离出来。在这里，我们定义了介导雷公藤红素抗炎活性的机制，并证明了饮食补充雷公藤红素对小鼠炎症驱动的致癌作用的化学预防效果。饮食中的雷公藤红素（在 8 周至 25 周龄的啮齿动物饮食中为 31.25ppm）可耐受良好，并可预防 C57BL/6 小鼠中 LPS 诱导的急性炎症，强烈抑制 LPS 诱导的诱导型一氧化氮合酶（iNOS）、环氧化酶（COX）-2、白细胞介素（IL）-6 和 IL-1β的诱导。为了测试饮食中的雷公藤红素是否抑制炎症驱动的结直肠癌（CRC），我们采用了一种独特的自发性炎症驱动 CRC 模型，该模型在具有 p27Kip1 基因种系缺失和 T 细胞特异性 Smad4 基因缺失（Smad4co/co；Lck-crep27Kip1-/-或 DKO）的小鼠中，早在 3 个月大时就会发生严重的肠道炎症和癌变。从 6 周龄开始，将 DKO 小鼠暴露于每日饮食中的雷公藤红素（饮食中 12.5ppm）可显著抑制结肠炎相关 CRC（CAC）的发展。在这种新的肠道肿瘤模型中，雷公藤红素对 CAC 的化学预防作用与 4 个月时 iNOS 的显著抑制有关，6 个月时 iNOS、COX-2 和 NFκB 的显著抑制，以及炎症细胞因子 IL-6 和 IL-1β的显著减少有关。在 C57BL/6 小鼠的氧化偶氮甲烷（AOM）加葡聚糖硫酸钠（DSS）诱导的致癌作用模型中，进一步证实了饮食中雷公藤红素对 CAC 的化学预防作用。这些数据表明，雷公藤红素作为一种安全有效的饮食补充剂，有可能用于人类 CAC 的化学预防。
