Diallyl Disulfide (DADS), a Constituent of Garlic, Inactivates NF-κB and Prevents Colitis-Induced Colorectal Cancer by Inhibiting GSK-3β.
Diallyl Disulfide (DADS), a Constituent of Garlic, Inactivates NF-κB and Prevents Colitis-Induced Colorectal Cancer by Inhibiting GSK-3β.
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DOI：
10.1158/1940-6207.capr-16-0044
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Kim YS
中科院分区：
文献类型：
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作者：
Saud SM;Li W;Gray Z;Matter MS;Colburn NH;Young MR;Kim YS
人们坚信大蒜具有药用特性，甚至可以降低患某些癌症（包括胃肠道癌症）的风险。大蒜的化学预防作用可能归因于大蒜含硫成分的抗炎特性，其中包括二烯丙基二硫化物（DADS）。在这里，我们证明 DADS 在结肠炎诱导的结直肠癌小鼠模型中预防结直肠肿瘤的发生。在化学致癌物氧化偶氮甲烷（AOM）和结肠刺激性葡聚糖硫酸钠（DSS）处理的FVB/N小鼠的饮食中添加85ppm DADS（每日60毫克人类等效剂量），导致肿瘤发生率、肿瘤数量和肿瘤负荷分别降低21.54%、47.3%和66.4%。进一步的分析显示，喂食添加 DADS 饮食的小鼠比喂食对照饮食的小鼠更快地解决了最初 DSS 诱导的炎症，从而防止了长期炎症和细胞转化。随后的体外机制研究表明 DADS 化学预防作用是通过 NFκB 信号传导介导的。当 SW480 结直肠癌细胞用 DADS 处理时，NFκB 核定位和活性减弱。有趣的是，NFκB 抑制被发现依赖于 DADS 对 GSK-3β（NFκB 的正调节因子）的抑制。在用添加了 85ppm DADS 的饮食喂养 AOM/DSS 处理的小鼠体内，也观察到 GSK-3β 的抑制和核 NFκB 活性的丧失。我们的结果表明，DADS 可以通过抑制炎症来预防肿瘤发生，这一过程主要涉及 GSK-3β 抑制以及随之而来的 NFκB 核定位的减少。
There is a strong belief that garlic has medicinal properties and may even reduce the risk of developing certain cancers including those of the gastrointestinal tract. The chemopreventive effects of garlic may be attributed to the anti-inflammatory properties of garlic’s sulfur-containing constituents, which includes diallyl disulfide (DADS). Here we demonstrate that DADS prevented colorectal tumorigenesis in a mouse model of colitis-induced colorectal cancer. Supplementation with 85ppm of DADS (60 mg daily human equivalent dose) in the diet of FVB/N mice treated with chemical carcinogen azoxymethane (AOM) and colonic irritant dextran sodium sulfate (DSS) resulted in the reduction in tumor incidence, tumor number and tumor burden by 21.54%, 47.3%, and 66.4%, respectively. Further analysis revealed that mice fed the DADS supplemented diet resolved the initial DSS-induced inflammation faster than those on the control diet, preventing prolonged inflammation and cellular transformation. Subsequent mechanistic studies in vitro suggest that DADS chemopreventive effects are mediated through NFκB signaling. When SW480 colorectal cancer cells were treated with DADS, NFκB nuclear localization and activity was diminished. Interestingly, NFκB suppression was found to be dependent on DADS inhibition of GSK-3β, a positive regulator of NFκB. Inhibition of GSK-3β and loss of nuclear NFκB activity were also observed in vivo in AOM/DSS treated mice fed a diet supplemented with 85ppm DADS. Our results indicate that DADS can prevent tumorigenesis by suppressing inflammation, a process largely involving GSK-3β inhibition and consequential reduction in NFκB nuclear localization.