Quercetin increased the antiproliferative activity of green tea polyphenol (-)-epigallocatechin gallate in prostate cancer cells.

We previously demonstrated that 50% of (−)-epigallocatechin gallate (EGCG) was present in methylated form (4″-MeEGCG) in human prostate tissue, which is less bioactive. We therefore investigated whether quercetin, a natural inhibitor of catechol-O-methyl transferase (COMT), will inhibit EGCG methylation leading to enhanced antiproliferative activity of EGCG in prostate cancer cells. Incubation with both, quercetin and EGCG, for 2 hr increased the cellular concentrations of EGCG by 4 to 8-fold and 6 to 10-fold in androgen-independent PC-3 cells and androgen-dependent LNCaP cells, respectively. Concurrently, the percent of 4″-MeEGCG in the total EGCG was decreased from 39% to 15% in PC-3 cells and from 61% to 38% in LNCaP cells. Quercetin and EGCG in combination synergistically inhibited cell proliferation, caused cell cycle arrest and induced apoptosis in PC-3 cells. In LNCaP cells EGCG and quercetin exhibited a stronger antiproliferative activity leading to an additive effect. The synergistic effect of these two agents in PC-3 cells could be based on the fact that EGCG primarily inhibited COMT activity while quercetin reduced the amount of COMT protein. In summary, quercetin combined with EGCG in vitro demonstrated enhanced inhibition of cell proliferation by increasing the intracellular concentration of EGCG and decreasing EGCG methylation.

我们先前证明，在人前列腺组织中，50%的（-）-表没食子儿茶素没食子酸酯（EGCG）以甲基化形式（4″ - MeEGCG）存在，其生物活性较低。因此，我们研究了槲皮素（一种儿茶酚 - O - 甲基转移酶（COMT）的天然抑制剂）是否会抑制EGCG甲基化，从而增强EGCG在前列腺癌细胞中的抗增殖活性。在雄激素非依赖性PC - 3细胞和雄激素依赖性LNCaP细胞中，槲皮素和EGCG共同孵育2小时，使EGCG的细胞浓度分别增加了4到8倍和6到10倍。同时，在PC - 3细胞中，4″ - MeEGCG在总EGCG中的百分比从39%降至15%，在LNCaP细胞中从61%降至38%。槲皮素和EGCG联合使用在PC - 3细胞中协同抑制细胞增殖，导致细胞周期停滞并诱导细胞凋亡。在LNCaP细胞中，EGCG和槲皮素表现出更强的抗增殖活性，产生相加效应。这两种药物在PC - 3细胞中的协同作用可能基于以下事实：EGCG主要抑制COMT活性，而槲皮素减少了COMT蛋白的量。总之，槲皮素与EGCG在体外联合使用通过增加EGCG的细胞内浓度和减少EGCG甲基化，显示出对细胞增殖更强的抑制作用。