Grape seed extract inhibits in vitro and in vivo growth of human colorectal carcinoma cells
Grape seed extract inhibits in vitro and in vivo growth of human colorectal carcinoma cells
复制标题
DOI：
10.1158/1078-0432.ccr-06-1465
复制
发表时间：
2006-10-15
影响因子：
11.5
通讯作者：
Agarwal, Chapla
中科院分区：
文献类型：
--
作者：
Kaur, Manjinder;Singh, Rana P.;Agarwal, Chapla
目的：越来越多的证据表明，水果和蔬菜的消费在降低各种癌症的风险，包括结肠直肠癌的有益作用。本文研究了富含原花青素的葡萄籽提取物（GSE）对结直肠癌的体内外抗癌作用及其机制。实验设计：观察GSE对培养的人大肠癌HT29和LoVo细胞增殖、细胞周期进展和凋亡的影响。研究了口服GSE对胸腺裸鼠HT29肿瘤异种移植物生长的体内影响。免疫组织化学分析异种移植物的增殖和凋亡情况。Western blot分析GSE与生物效应相关的分子变化。结果：GSE （25-100 μ g/mL）对细胞生长有明显的剂量依赖性和时间依赖性抑制作用，同时细胞死亡增加。GSE诱导G(1)期细胞周期阻滞，Cip1/p21蛋白水平显著升高，G(1)期相关细胞周期蛋白和细胞周期蛋白依赖激酶显著降低。gse诱导的细胞死亡以凋亡为主，并伴有caspase-3激活。200 mg/kg剂量的GSE对小鼠的肿瘤生长具有时间依赖性的抑制作用，且无任何毒性，8周后每只小鼠的肿瘤体积减少44%。GSE抑制肿瘤细胞增殖，但增加凋亡细胞死亡。gse处理的肿瘤还显示Cip1/p21蛋白水平和聚（adp -核糖）聚合酶裂解增强。结论：GSE可能是一种有效的结直肠癌化学预防药物，GSE对结直肠癌的生长抑制和凋亡作用可能通过上调Cip1/p21介导。
Purpose: Accumulating evidences suggest the beneficial effects of fruit-and-vegetable consumption in lowering the risk of various cancers, including colorectal cancer. Herein, we investigated the in vitro and in vivo anticancer effects and associated mechanisms of grape seed extract (GSE), a rich source of proanthocyanidins, against colorectal cancer.Experimental Design: Effects of GSE were examined on human colorectal cancer HT29 and LoVo cells in culture for proliferation, cell cycle progression, and apoptosis. The in vivo effect of oral GSE was examined on HT29 tumor xenograft growth in athymic nude mice. Xenografts were analyzed by immunohistochemistry for proliferation and apoptosis. The molecular changes associated with the biological effects of GSE were analyzed by Western blot analysis.Results: GSE (25-100 mu g/mL) causes a significant dose- and time-dependent inhibition of cell growth with concomitant increase in cell death. GSE induced G(1) phase cell cycle arrest along with a marked increase in Cip1/p21 protein level and a decrease in G(1) phase-associated cyclins and cyclin-dependent kinases. GSE-induced cell death was apoptotic and accompanied by caspase-3 activation. GSE feeding to mice at 200 mg/kg dose showed time-dependent inhibition of tumor growth without any toxicity and accounted for 44% decrease in tumor volume per mouse after 8 weeks of treatment. GSE inhibited cell proliferation but increased apoptotic cell death in tumors. GSE-treated tumors also showed enhanced Cip1/p21 protein levels and poly (ADP-ribose) polymerase cleavage.Conclusions: GSE may be an effective chemopreventive agent against colorectal cancer, and that growth inhibitory and apoptotic effects of GSE against colorectal cancer could be mediated via an up-regulation of Cip1/p21.