Inhibitory effects of 5-hydroxy polymethoxyflavones on colon cancer cells
Inhibitory effects of 5-hydroxy polymethoxyflavones on colon cancer cells
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DOI：
10.1002/mnfr.200900605
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发表时间：
2010-07-01
影响因子：
5.2
通讯作者：
Xiao, Hang
中科院分区：
文献类型：
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作者：
Qiu, Peiju;Dong, Ping;Xiao, Hang
羟基聚甲氧基黄酮类化合物(PMF)是一类主要存在于柑橘类植物中的新型类黄酮化合物。我们研究了三种主要的5-羟基PMF，即：5-羟基-6，7，8，3‘，4’-五甲氧基黄酮，5-羟基-3，6，7，8，3‘，4’-六甲氧基黄酮和5-羟基-6，7，8，4‘-四甲氧基黄酮对人结肠癌HCT116和HT29细胞的作用。将它们的作用与其全甲氧基化的对应物，即：nobiletin，3，5，6，7，8，3‘，4’-七甲氧基黄酮和橘皮素进行了比较。5-羟基PMF对结肠癌细胞生长的抑制作用明显强于过甲氧基化的PMF，提示5-羟基在增强5-羟基PMF的抑制活性中起着关键作用。流式细胞仪分析显示，三种5-羟基PMF对细胞周期和细胞凋亡的影响不同，这可能表明三种5-羟基PMF的作用机制不同。例如，5-羟基-6，7，8，3‘，4’-五甲氧基黄酮使HT29细胞周期停滞于G2/M期，而5-羟基-3，6，7，8，3‘，4’-六甲氧基黄酮引起明显的G0/G1期阻滞。相反，5-羟基-6，7，8，4‘-四甲氧基黄酮增加了亚G0/G1期细胞，这已被证实是由于促进了细胞凋亡。我们的结果进一步表明，5-羟基PMF的抑制作用与其调控与细胞增殖和凋亡相关的关键信号蛋白有关，如p21(Cip1/Waf1)、CDK-2、CDK-4、磷酸化Rb、Mcl-1、caspase3和8以及多聚ADP核糖聚合酶(PARP)。
Hydroxylated polymethoxyflavones (PMFs) are a class of novel flavonoid compounds mainly found in citrus plants. We studied the effects of three major 5-hydroxy PMFs, namely: 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone, 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone, and 5-hydroxy-6,7,8,4'-tetramethoxyflavone, on human colon cancer HCT116 and HT29 cells. Their effects were compared with those produced by their permethoxylated counterparts, namely: nobiletin, 3,5,6,7,8,3',4'-heptamethoxylflavone, and tangeretin. 5-Hydroxy PMFs showed much stronger inhibitory effects on the growth of the colon cancer cells in comparison with their permethoxylated counterparts, suggesting the pivotal role of hydroxyl group at 5-position in the enhanced inhibitory activity by 5-hydroxy PMFs. Flow cytometry analysis demonstrated that three 5-hydroxy PMFs produced different effects on the cell cycle and apoptosis, which may suggest that three 5-hydroxy PMFs act through different mechanisms. For example, 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone caused cell cycle arrest at G2/M phase in HT29 cells, while 5-hydroxy3,6,7,8,3',4'-hexamethoxyflavone led to significant G0/G1 phase arrest. In contrast, 5-hydroxy-6,7,8,4'-tetramethoxyflavone increased sub-G0/G1 cell population, which has been confirmed to be due to enhanced apoptosis. Our results further demonstrated that the inhibitory effects of 5-hydroxy PMFs were associated with their ability in modulating key signaling proteins related to cell proliferation and apoptosis, such as p21(Cip1/Waf1), CDK-2, CDK-4, phosphor-Rb, Mcl-1, caspases 3 and 8, and poly ADP ribose polymerase (PARP).