Chemoprevention of familial adenomatous polyposis by natural dietary compounds sulforaphane and dibenzoylmethane alone and in combination in APCMin/+ mouse
Chemoprevention of familial adenomatous polyposis by natural dietary compounds sulforaphane and dibenzoylmethane alone and in combination in APCMin/+ mouse
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DOI：
10.1158/0008-5472.can-07-1112
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Kong, Ah-Ng Tony
中科院分区：
文献类型：
--
作者：
Shen, Guoxiang;Khor, Tin Oo;Kong, Ah-Ng Tony
化学防癌剂萝卜硫烷(SFN)和二苯甲酰甲烷(DBM)在几种啮齿动物致癌模型中显示出抗肿瘤作用。在这项研究中，我们在APC(Min/+)小鼠模型上研究了SFN和DBM单独或联合应用对癌症的化学预防作用和潜在的分子机制。5周龄雄性APC(Min/+)小鼠(每组12只)分别给予对照AIN-76A饲料、含600ppm SFN和1.0%DBM的饲料，或300ppm SFN和0.5%DBM的混合饲料，共10周。然后处死小鼠，检查肿瘤的数量和大小。采用基因芯片分析、Western blotting、ELISA法和免疫组织化学染色等方法，探讨SFN和DBM化学预防肿瘤的分子机制。单独或联合应用三七总皂苷和DBM可显著抑制小鼠肠腺瘤的生长，抑制率分别为48%(P=0.002)、50%(P=0.001)和57%(P<；0.001)。日粮中添加600ppmSFN和1.0%DBM可使小鼠结肠肿瘤数分别减少80%(P=0.016)和60%(P=0.103)，而SFN和DBM联合应用则抑制了肿瘤的生长(P=0.002)。SFN和DBM治疗均可降低肠息肉或表面正常粘膜中前列腺素E-2或白三烯B-4的水平。治疗还导致细胞存活和生长相关的信号通路(如Akt和细胞外信号调节激酶)或生物标记物(如环氧合酶-2、增殖细胞核抗原、裂解的caspase、细胞周期蛋白d1和p21)的抑制。综上所述，我们的结果表明，SFN和DBM单独以及它们的组合都是化学预防胃肠道癌症的有效天然饮食化合物。
Cancer chemopreventive agent sulforaphane (SFN) and dibenzoylmethane (DBM) showed antitumorigenesis effects in several rodent carcinogenesis models. In this study, we investigated the cancer chemopreventive effects and the underlying molecular mechanisms of dietary administration of SFN and DBM alone or in combination in the Apc(Min/+) mice model. Male Apc(Min/+) mice (12 per group) at age of 5 weeks were given control AIN-76A diet, diets containing 600 ppm SFN and 1.0% DBM, or a combination of 300 ppm SFN and 0.5% DBM for 10 weeks. Mice were then sacrificed, and tumor numbers and size were examined. Microarray analysis, Western blotting, ELISA, and immunohistochemical staining were done to investigate the underlying molecular mechanisms of cancer chemopreventive effects of SFN and DBM. Dietary administrations of SFN and DBM alone or in combination significantly inhibited the development of intestinal adenomas by 48% (P = 0.002), 50% (P = 0.001), and 57% (P < 0.001), respectively. Dietary administration of 600 ppm SFN and 1.0% DBM also reduced colon tumor numbers by 80% (P = 0.016) and 60% (P = 0.103), respectively, whereas the combination of SFN and DBM treatment blocked the colon tumor development (P = 0.002). Both SFN and DBM treatments resulted in decreased levels of prostaglandin E-2 or leukotriene B-4 in intestinal polyps or apparently normal mucosa. Treatments also led to the inhibition of cell survival and growth-related signaling pathways (such as Akt and extracellular signal-regulated kinase) or biomarkers (such as cyclooxygenase-2, proliferating cell nuclear antigen, cleaved caspases, cyclin D1, and p21). In conclusion, our results showed that both SFN and DBM alone as well as their combination are potent natural dietary compounds for chemoprevention of gastrointestinal cancers.