Inhibition of the growth of premalignant and malignant human oral cell lines by extracts and components of black raspberries
Inhibition of the growth of premalignant and malignant human oral cell lines by extracts and components of black raspberries
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DOI：
10.1207/s15327914nc5102_11
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发表时间：
2005-01-01
影响因子：
2.9
通讯作者：
D'Ambrosio, SM
中科院分区：
文献类型：
--
作者：
Han, CH;Ding, HM;D'Ambrosio, SM
黑树莓是化学预防植物化学物质的丰富天然来源。最近的研究表明，冻干黑树莓抑制啮齿动物口腔癌、食管癌和结肠癌的发展，黑树莓提取物抑制苯并（a）芘诱导的仓鼠胚胎成纤维细胞的细胞转化。然而，黑树莓化学预防的分子机制和活性成分尚不清楚。在这项研究中，我们发现，黑树莓，阿魏酸和β-谷甾醇的2个主要的化学预防成分，以及在硅胶柱层析过程中用乙醇洗脱的馏分（RO-ET）的有机提取物的冻干黑树莓抑制癌前和恶性，但不是正常的人类口腔上皮细胞系的生长。用CH 2 O2/乙醇（DM：ET）和鞣花酸洗脱的另一个组分抑制正常以及癌前和恶性人类口腔细胞系的生长。我们调查的分子机制，阿魏酸和β-谷甾醇和RO-ET馏分选择性地抑制癌前和恶性口腔细胞的生长，使用流式细胞术和细胞周期调控蛋白的Western印迹。用RO-ET组分处理细胞后，细胞周期分布没有明显变化。与阿魏酸孵育后，癌前和恶性细胞重新分布到细胞周期的G（2）/M期。β-谷甾醇处理的癌前和恶性细胞分别在G（0）/G（1）和G（2）/M期聚集。RO-ET组分降低了癌前细胞中的细胞周期蛋白A和细胞分裂周期基因2（cdc 2）以及恶性细胞系中的细胞周期蛋白B1、细胞周期蛋白D1和cdc 2的水平。该组分还升高了恶性细胞系中P2.1（waf 1/cip 1）的水平。阿魏酸处理导致两种细胞系中细胞周期蛋白B1和cdc 2的水平增加，并且在恶性细胞系中诱导p21（waf 1/cip 1）。β-谷甾醇降低了癌前和恶性细胞系中细胞周期蛋白B1和cdc 2的水平，同时增加了p21（waf 1/cip 1）。这些结果首次表明，黑树莓对癌前和恶性人类口腔细胞的生长抑制作用可能存在于靶向调节细胞周期进程的异常信号通路的特定组分中。
Black raspberries tire a rich natural source of chemopreventive phytochemicals. Recent studies have shown that freeze-dried black raspberries inhibit the development of oral, esophageal, and colon cancer in rodents, and extracts of black raspberries inhibit benzo(a)pyrene-induced cell transformation of hamster embryo fibroblasts. However the molecular mechanisms and the active components responsible for black raspberry chemoprevention are unclear. In this study, we found that 2 major chemopreventive components of black raspberries, ferulic acid and beta-sitosterol, and a fraction eluted with ethanol (RO-ET) during silica column chromatography of the organic extract of freeze-dried black raspberries inhibit the growth of premalignant and malignant but not normal human oral epithelial cell lines. Another fraction eluted with CH2O2/ethanol (DM:ET) and ellagic acid inhibited the growth of normal as well as premalignant and malignant human oral cell lines. We investigated the molecular mechanisms by which ferulic acid and beta-sitosterol and the RO-ET fraction selectively inhibited the growth of premalignant and malignant oral cells using flow cytometry and Western blotting of cell cycle regulatory proteins. There was no discernable change in the cell cycle distribution following treatment of cells with the RO-ET fraction. Premalignant and malignant cells redistributed to the G(2)/M phase of the cell cycle following incubation with ferulic acid. beta-sitosterol treated premalignant and malignant cells accumulated in the G(0)/G(1) and G(2)/M phases, respectively. The RO-ET fraction reduced the levels of cyclin A and cell division cycle gene 2 (cdc2) in premalignant cells and cyclin B1, cyclin D1, and cdc2 in the malignant cell lines. This fraction also elevated the levels of P2.1(waf1/cip1) in the malignant cell line. Ferulic acid treatment led to increased levels of cyclin B1 and cdc2 in both cell lines, and p21(waf1/cip1) was induced in the malignant cell line. beta-sitosterol reduced the levels of cyclin B1 and cdc2 while increasing p21(waf1/cip1) in both the premalignant and malignant cell lines. These results show for the first time that the growth inhibitory effects of black raspberries on premalignant and malignant human oral cells may reside in specific components that target aberrant signaling pathways regulating cell cycle progression.