Chemoprevention against colon cancer by dietary intake of sulforaphane
Chemoprevention against colon cancer by dietary intake of sulforaphane
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DOI：
10.31989/ffhd.v9i6.607
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发表时间：
2019-07
影响因子：
1
通讯作者：
A. Yanaka;Hideo Suzuki;M. Mutoh;T. Kamoshida;N. Kakinoki;S. Yoshida;M. Hirose;Tsugio Ebihara;I. Hyodo
中科院分区：
文献类型：
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作者：
A. Yanaka;Hideo Suzuki;M. Mutoh;T. Kamoshida;N. Kakinoki;S. Yoshida;M. Hirose;Tsugio Ebihara;I. Hyodo
背景资料：萝卜硫素（Sulforaphane，SFN）属于异硫氰酸酯家族，在西兰花芽中大量存在，通过nrf 2-keap 1途径诱导多种抗氧化酶活性，从而保护细胞免受各种氧化应激的损伤。我们先前已经证明SFN保护胃粘膜免受H.幽门感染SFN还下调组蛋白去乙酰化酶（HDAC）活性，从而诱导多种组织中的肿瘤细胞凋亡并抑制其增殖。另一方面，结肠癌在日本一直在增加。由于大量流行病学研究表明结肠癌与抗氧化蔬菜的摄入量呈负相关，因此我们研究了膳食SGS是否可以预防小鼠和人类受试者的结肠肿瘤发生。方法：1。SFN对用化学致癌物处理的小鼠的结肠肿瘤发生的影响：在用化学致癌物氧化偶氮甲烷（AOM）（15 mg/kg）预处理的ICR雄性小鼠中检查SFN对结肠肿瘤发生的影响。AOM处理的小鼠在有或没有萝卜硫素芥子油苷（SGS：2，200 ppm/kg/天）的情况下喂养8周，萝卜硫素芥子油苷是SFN的前体。评价SGS处理对显微镜下异常隐窝灶（ACF）形成和结肠粘膜中肉眼可见肿瘤的影响。2. SFN对结肠腺瘤患者结肠异常隐窝病灶（ACF）形成的影响：通过结肠镜检查结肠腺瘤患者摄入生西兰花芽（BS），50 g/天，每隔一天含有220 mg SGS，持续6个月对直肠粘膜ACF数量变化的影响。3. SFN对人类受试者肠道微生物群的影响：通过使用T-RFLP方法测量粪便细菌的组成来评估饮食摄入生西兰花芽（BS）（20 g/天，每隔一天含有88 mg SGS）2周对健康志愿者肠道微生物群的影响。在人类研究中，不含SFN的苜蓿芽被用作安慰剂对照。结果：1.每日给予SGS抑制AOM预处理小鼠体内显微镜下ACF和肉眼可见结肠肿瘤的形成。2.服用BS 6个月后，结肠腺瘤患者结肠ACF数量减少。3.摄入BS 2周可增加双歧杆菌和Clostridium XVIa的百分比，这已被证明通过增加结肠腔中丁酸的产生来增强结肠粘膜的保护。SFN可能通过上调正常结肠上皮细胞中的nrf 2依赖性抗氧化酶，以及通过抑制HDAC活性诱导结肠肿瘤细胞凋亡来提供针对结肠癌的化学保护。本研究进一步提示SFN引起的肠道菌群变化可能在结肠癌的化学预防中发挥作用。关键词：萝卜硫素，结肠癌，化学预防，异常隐窝灶，肠道菌群
Background: Sulforaphane (SFN), a phytochemical compound, which belongs to isothiocyanates family found in abundance in broccoli sprouts, potently induces a variety of antioxidant enzymes via nrf2-keap1 mediated pathway, thereby protects cells from injury induced by various kinds of oxidative stresses. We have previously shown that SFN protects gastric mucosa from oxidative injury induced by H. pylori infection. SFN also down-regulates histone deacetylase (HDAC) activity, thereby induces apoptosis and inhibits proliferation of tumor cells in variety of tissues. On the other hand, colon cancer has been increasing in Japan. Since numerous epidemiological studies have shown that colon cancer is inversely associated with intake of anti-oxidant vegetables, we examined if dietary SGS prevents colon tumorigenesis in mice, and in human subjects.Methods: 1. Effects of SFN on Colonic tumorigenesis in Mice Treated with Chemical Carcinogen: Effects of SFN on colonic tumorigenesis were examined in the ICR male mice, pretreated with a chemical carcinogen, azoxymethane (AOM) (15 mg/kg). The AOM-treated mice were fed for 8 weeks with or without sulforaphane glucosinolates (SGS: 2,200 ppm/kg/day), which is a precursor of SFN. Effects of SGS treatment on formation of the microscopic aberrant crypt foci (ACF), and the macroscopic tumors in colonic mucosa were evaluated. 2. Effects of SFN on formation of Colonic Aberrant Crypt Foci (ACF) in patients with colonic adenoma: Effects of intake of raw broccoli sprouts (BS), 50 g/day, which contains 220 mg SGS every other day, for 6 months on changes in the number of ACF in rectal mucosa was examined by colonoscopy in patients with colonic adenoma. 3. Effects of SFN on intestinal microbiota in human subjects: Effects of dietary intake of raw broccoli sprouts (BS), 20 g/day, which contains 88 mg SGS every other day, for 2 weeks on intestinal microbiota in healthy volunteers was assessed by measuring composition of stool bacteria, using T-RFLP method. In human studies, alfalfa sprouts, which contains no SFN was used as a placebo control. Results: 1. Daily administration of SGS suppressed formation of microscopic ACF and macroscopic colonic tumors in the AOM-pretreated mice in vivo. 2. Intake of BS for 6 months tended to decrease the number of colonic ACF in patients with colonic adenoma. 3. Intake of BS for 2 weeks increased percentages of Bifidobacterium and Clostridium XVIa, which has been shown to enhance protection of colonic mucosa by increasing butyrate production in colonic lumen.Conclusions: 1. SFN affords chemoprotection against colonic cancer, presumably by up-regulating nrf2-dependent antioxidant enzymes in normal colonic epithelial cells, and by inducing apoptosis of colonic tumor cells through inhibition of HDAC activity. The present study further suggests that changes in intestinal microbiota by SFN, may play a role in chemoprevention against colon cancer.Keywords: sulforaphane, colon cancer, chemoprevention, aberrant crypt foci, intestinal microbiota