蘋果多酚抑制乳癌轉移之作用

Apple polyphenols inhibit breast cancer metastasis

陳盈均

乳癌 ； 腫瘤轉移 ； 蘋果多酚 ； Breast cancer ； Metastasis ； Apple polyphenol ； Focal adhesion kinase

中山醫學大學生化微生物免疫研究所學位論文

2016年

碩士

李彗禎

繁體中文

根據過去文獻指出：蘋果多酚在多種癌症上具有抗腫瘤的效果，但是蘋果多酚對於是否能夠影響乳癌腫瘤轉移則尚未釐清。因此，在本次實驗中，將探討蘋果多酚是否對乳癌細胞：MCF-7、MDA-MB-231、MDA-MB-453之轉移具有抑制的效果。本實驗結果顯示：蘋果多酚在濃度小於0.2mg/ml時，對於乳癌細胞的存活並沒有顯著性的差異，但是蘋果多酚卻能有效的抑制乳癌細胞之移動與侵犯的特性。另外，結果發現蘋果多酚可以抑制細胞黏附分子FAK蛋白表現及影響下游訊號傳遞蛋白如Paxillin、Akt、PI3K以及mTOR等，進而影響細胞的黏附及細胞轉移。為了更進一步確定蘋果多酚在臨床上抑制乳癌轉移的可行性，因此，將目前臨床乳癌用藥：紫杉醇與蘋果多酚合併使用，並發現有加乘效果。實驗結果也證明蘋果多酚與紫杉醇合併使用時，抑制FAK的表現能力是比單一使用蘋果多酚或紫杉醇更為顯著的。另外，利用動物模式之活體腫瘤移植模型，將小鼠乳癌細胞4T1經由尾靜脈注射隻小鼠體內，結果顯示蘋果多酚可抑制腫瘤生長與降低轉移能力。綜合本次實驗結果，我們首先發現蘋果多酚藉由降低FAK，進而影響下游傳遞訊息，達到抑制乳癌腫瘤移動與侵犯能力的效果。而在動物實驗中，也發現相同結果，其次，我們發現在紫杉醇與蘋果多酚合併使用時，對於抑制FAK及其下游傳遞訊息的效果為更加顯著的。

Apple polyphenol (AP) has been reported to possess to potent anti-tumor activity on different kinds of cancers, but the effects of AP on metastatic capability of breast cancer is not clarified. Herein, we aimed to investigate inhibitory effects of AP on breast cancer cells. Our results showed that AP treatments won’t significantly affect cell viability of breast cancer cells MCF-7, MDA-MB-231 and MDA-MB-453 but suppress migration and invasion of the cells when the AP concentration under 0.2mg/ml. Interestingly, we found that AP treatments reduced expression of focal adhesion kinase (FAK). Besides, the activation of FAK downstream effectors such as Paxillin, PI3K, Akt and mTOR were also inhibited by AP treatments. To facilitate further research on the feasibility of a clinically effect on breast cancer metastasis of AP, we examine the effect of co-treatment with Paclitaxel and AP. Paclitaxel is an important agent in the treatment of breast cancer. It is necessary to know whether co-treatment with a commonly applied drug and AP has a synergistic effect. Here, we present a detailed study about the effects of AP co-treated with Paclitaxel. We further demonstrated that inhibition of FAK expression by co-treating with AP and paclitaxel was more significant than AP-only treatment or paclitaxel-only treatment. We also showed that co-treatment with AP and paclitaxel suppressed FAK signaling pathway and FAK downstream effectors. To validate the suppressive effects of AP, we used a isograft model to clarify. We injected 4T1 cells into ICR mice through tail vein and observed the suppressive metastasis effects and tumorigenesis of AP treatments. Collectively, these findings indicate that AP treatments significantly inhibited invasion of MCF-7, MDA-MB-231 and MDA-MB-453 cells through reducing expression of FAK. There is the same result that AP suppressed metastasis and tumorigenesis in vivo. However, co-treatment with AP and paclitaxel shows more effective than single use on inhibiting FAK pathway.

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