Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Aurora, CO 80045, USA.
Neoplasia. 2010 Jan;12(1):95-102. doi: 10.1593/neo.91718.
Chemopreventive effects and associated mechanisms of grape seed extract (GSE) against intestinal/colon cancer development are largely unknown. Herein, we investigated GSE efficacy against intestinal tumorigenesis in APC(min/+) mice. Female APC(min/+) mice were fed control or 0.5% GSE (wt/wt) mixed AIN-76A diet for 6 weeks. At the end of the experiment, GSE feeding decreased the total number of intestinal polyps by 40%. The decrease in polyp formation in the small intestine was 42%, which was mostly in its middle (51%) and distal (49%) portions compared with the proximal one. GSE also decreased polyp growth where the number of polyps of 1 to 2 mm in size decreased by 42% and greater than 2 mm in size by 71%, without any significant change in polyps less than 1 mm in size. Immunohistochemical analyses of small intestinal tissue samples revealed a decrease (80%-86%) in cell proliferation and an increase (four- to eight-fold) in apoptosis. GSE feeding also showed decreased protein levels of cyclooxygenase-2 (COX-2) (56%-64%), inducible nitric oxide synthase (iNOS) (58%-60%), and beta-catenin (43%-59%) but an increased Cip1/p21-positive cells (1.9- to 2.6-fold). GSE also decreased cyclin D1 and c-Myc protein levels in small intestine. Together, these findings show the chemopreventive potential of GSE against intestinal polyp formation and growth in APC(min/+) mice, which was accompanied with reduced cell proliferation and increased apoptosis together with down-regulation in COX-2, iNOS, beta-catenin, cyclin D1, and c-Myc expression, but increased Cip1/p21. In conclusion, the present study suggests potential usefulness of GSE for the chemoprevention of human intestinal/colorectal cancer.
葡萄籽提取物（GSE）对肠道/结肠癌发展的化学预防作用及其相关机制在很大程度上尚不清楚。在此，我们研究了 GSE 对 APC(min/+)小鼠肠道肿瘤发生的疗效。雌性 APC(min/+)小鼠喂食对照或 0.5% GSE（wt/wt）混合 AIN-76A 饮食 6 周。实验结束时，GSE 喂养使肠道息肉总数减少了 40%。小肠息肉形成减少了 42%，与近端相比，主要在中部（51%）和远端（49%）。GSE 还减少了息肉生长，大小为 1 至 2 毫米的息肉数量减少了 42%，大于 2 毫米的息肉数量减少了 71%，而小于 1 毫米的息肉数量没有明显变化。小肠组织样本的免疫组织化学分析显示细胞增殖减少（80%-86%），细胞凋亡增加（4 至 8 倍）。GSE 喂养还显示环氧合酶-2（COX-2）（56%-64%）、诱导型一氧化氮合酶（iNOS）（58%-60%）和β-连环蛋白（43%-59%）的蛋白水平降低，但 Cip1/p21 阳性细胞增加（1.9-至 2.6 倍）。GSE 还降低了小肠中环细胞周期蛋白 D1 和 c-Myc 的蛋白水平。总之，这些发现表明 GSE 对 APC(min/+)小鼠肠道息肉形成和生长具有化学预防潜力，这伴随着细胞增殖减少和凋亡增加，同时 COX-2、iNOS、β-连环蛋白、cyclin D1 和 c-Myc 表达下调，但 Cip1/p21 增加。总之，本研究表明 GSE 对人类肠道/结直肠癌的化学预防具有潜在的应用价值。
