Quercetin Enhances Tamoxifen-Induced Antitumor Activity through Down-Regulation of Cyclin E2 Expression in Drug-Resistant Human Breast Cancer Cells

槲黃素透過細胞週期蛋白Cyclin E2的抑制作用增強對Tamoxifen抗藥性乳癌細胞之抗癌作用

杜世興(Shih-Hsin Tu) ； 楊國卿(Kuo-Ching Yang) ； 何其儻(Chi-Tang Ho) ； 黃清水(Ching-Shui Huang) ； 陳清祥(Ching-Shyang Chen) ； 張慧文(Hui-Wen Chang) ； 張鑑熹(Chien-Hsi Chang) ； 吳志雄(Chih-Hsiung Wu) ； 何元順(Yuan-Soon Ho)

《台灣癌症醫學雜誌》 29卷4期 (2013/10) Pp. 167-181

https://doi.org/10.6323/JoCRP.2013.29.4.1

摘要

目的：槲黃素（quercetin）可以在許多植物組織中發現，是一種類黃酮成分。槲黃素的抗乳癌作用主要是化學預防與作為化學治療藥物的增強作用。至於它在乳癌細胞內真正作用於何種致癌蛋白並未有任何報導。材料方法：本實驗利用即時反轉錄酶鏈鎖反應（real-time reverse-transcriptase polymerase chain reaction）分析細胞週期蛋白cyclin E2（CCNE2）mRNA在213位乳癌病人身上的表現情況，並利用MCF7乳癌細胞株作為研究模式，探討槲黃素之抑制CCNE2的作用機制。結果：證實CCNE2 mRNA在癌組織中的表現明顯高於正常組織約3.55倍（*P = 0.005）。證實CCNE2蛋白在Tamoxifen抗藥性MCF-7細胞株（TAM-R）中，CCNE2高表現。此種TAM-R細胞株CCNE2高表現可以被槲黃素（5 μM）所抑制。合併處理槲黃素與Tamoxifen可以使抗藥性MCF-7細胞株對藥物的敏感度增加。結論：槲黃素有潛力與Tamoxifen作為合併使用，可以使抗藥性MCF-7細胞株對藥物的敏感度增加，並增加化療效果解決乳癌病人抗藥性的問題。

關鍵字

槲黃素 ； 細胞週期蛋白cyclin E2 ； 乳癌 ； 諾瓦得士錠 ； 細胞週期

並列摘要

Quercetin is found in plant tissues known as flavonoids, and contains properties that act as a chemopreventive or chemosensitizer agent against human breast cancer. However, the oncogenic molecule inhibited by quercetin treatment has still not been identified in human breast cancer cells. The cyclin E2 (CCNE2) mRNA levels were demonstrated to be higher in tumor cells (3.55-fold, *P = 0.005) than in normal paired tissue samples, using real-time reversetranscriptase polymerase chain reaction (RT-PCR) analysis (n = 213). We further demonstrated that relatively higher levels of CCNE2 protein expression were detected in the tamoxifenresistant (TAM-R) MCF-7 cells. The results showed that CCNE2 protein expression levels were specifically inhibited in quercetin-treated (5 μM) TAM-R cells, either in the presence or absence of 4-OH-TAM (100 nM). Additionally, it was noted that combination treatment with 4-OH-TAM and quercetin significantly sensitized TAM-R cells to 4-OH-TAM. This study suggests that quercetin can be used as a chemosensitizer by targeting CCNE2 expression levels, which may be a novel strategy to overcome TAM resistance in breast cancer patients.

並列關鍵字

quercetin ； CCNE2 ； breast cancer ； tamoxifen ； cell cycle