The chemopreventive effect of 5-demethylnobiletin, a unique citrus flavonoid, on colitis-driven colorectal carcinogenesis in mice is associated with its colonic metabolites
The chemopreventive effect of 5-demethylnobiletin, a unique citrus flavonoid, on colitis-driven colorectal carcinogenesis in mice is associated with its colonic metabolites
复制标题
5-去甲基川陈皮素（一种独特的柑橘类黄酮）对小鼠结肠炎驱动的结直肠癌的化学预防作用与其结肠代谢物有关
DOI：
10.1039/d0fo00616e
复制
发表时间：
2020-06-01
期刊：
影响因子：
6.1
通讯作者：
Xiao, Hang
中科院分区：
文献类型：
--
作者：
Song, Mingyue;Lan, Yaqi;Xiao, Hang
5-去甲基川陈皮素 (5DN) 是一种独特的黄酮类化合物，主要存在于柑橘类水果中。在这项研究中，我们确定了 5DN 及其主要结肠代谢物对结肠炎驱动的结肠癌小鼠模型和人类结肠癌细胞模型的化学预防作用。在氧化偶氮甲烷/硫酸葡聚糖钠处理的小鼠中，膳食 5DN（膳食中 0.05% w/w）显着降低肿瘤发生率、多样性和负荷，并在小鼠结肠组织中显示出有效的抗增殖、促凋亡和抗炎活性。在5DN处理小鼠的结肠粘膜中发现了5DN的三种主要代谢物，分别为5,3'-二去甲基川陈皮素（M1）、5,4'-二去甲基川陈皮素（M2）和5,3',4'-三去甲基川陈皮素（M3），并且这些代谢物在小鼠结肠粘膜中的总水平比5DN高1.56倍。细胞培养研究表明，5DN 及其结肠代谢物通过诱导细胞周期停滞、触发细胞凋亡以及调节与细胞增殖和凋亡相关的关键信号蛋白来深刻抑制人结肠癌细胞的生长。重要的是，结肠代谢物，尤其是 M1，显示出比 5DN 本身产生的作用更强的作用。总体而言，我们的结果表明，膳食 5DN 显着抑制小鼠结肠炎驱动的结肠癌发生，并且这种化学预防作用与其在结肠中的代谢物有关。
5-Demethylnobiletin (5DN) is a unique flavonoid mainly found in citrus fruits. In this study, we determined the chemopreventive effects of 5DN and its major colonic metabolites on both a colitis-driven colon carcinogenesis mouse model and a human colon cancer cell model. In azoxymethane/dextran sulfate sodium-treated mice, dietary 5DN (0.05% w/w in the diet) significantly decreased the tumor incidence, multiplicity and burden, and showed potent anti-proliferative, proapoptotic, and anti-inflammatory activities in mouse colon tissue. Three major metabolites of 5DN, named 5,3 '-didemethylnobiletin (M1), 5,4 '-didemethylnobiletin (M2) and 5,3 ',4 '-tridemethylnobiletin (M3), were found in the colonic mucosa of 5DN-treated mice, and the combined level of these metabolites in mouse colonic mucosa was 1.56-fold higher than that of 5DN. Cell culture studies revealed that 5DN and its colonic metabolites profoundly inhibited the growth of human colon cancer cells by inducing cell cycle arrest, triggering apoptosis and modulating key signaling proteins related to cell proliferation and apoptosis. Importantly, the colonic metabolites, especially M1, showed much stronger effects than those produced by 5DN itself. Overall, our results demonstrated that dietary 5DN significantly inhibited colitis-driven colon carcinogenesis in mice, and this chemopreventive effect was associated with its metabolites in the colon.