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研究生:連喬瑩
研究生(外文):Chiao-Ying Lien
論文名稱:Sulforaphane在人類乳癌細胞調控AKT/mTOR/S6K路徑之探討
論文名稱(外文):Sulforaphane regulates AKT/mTOR/S6K pathway in human breast cancer cells
指導教授:吳志中吳志中引用關係
指導教授(外文):Chin-Chung Wu
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:天然藥物研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:85
中文關鍵詞:乳癌sulforaphaneAKTmTORtamoxifen
外文關鍵詞:breast cancersulforaphaneAKTmTORtamoxifen
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乳癌是全球在女性腫瘤疾病中發生最為普遍且具有第二高致死率的癌症。Tamoxifen (TM) 是乳癌的賀爾蒙療法中主要之藥物,但在目前臨床情況,已將近一半的乳癌患者無法受益於TM的治療效果,因此TM的抗藥性問題在乳癌的治療措施中將是個重要的議題。Sulforaphane (SFN) 是一個自十字花科植物分離出的化合物,已有相當多研究指出其具有抗癌的潛力和使癌細胞對化學治療敏感化。在本篇研究中,我們測試SFN對雌激素受體陽性乳癌細胞株MCF-7以及三陰性乳癌MDA-MB-468之細胞毒性,結果顯示SFN能夠濃度相關地抑制MDA-MB-468和MCF-7的細胞存活率。在機轉研究上,SFN在兩株乳癌細胞上皆能影響PDK1、AKT、mTOR、S6K和S6的磷酸化。另外,本篇實驗也發現以低濃度的SFN與TM合併使用於兩株細胞皆可以增加TM的細胞毒性,並且可以更顯著的抑制AKT、mTOR、S6K和S6的磷酸化。綜合研究結果顯示,SFN可以由抑制乳癌細胞的AKT/mTOR/S6K路徑導致細胞凋亡,而將SFN合併TM也可因抑制AKT/mTOR/S6K路徑而增加後者的抗癌活性。

Breast cancer is the most common cancer and the second leading cause of cancer-related deaths among women worldwide. Tamoxifen (TM) has been a mainstay of endocrine therapy for both early and advanced breast cancer patients for approximately four decades. In clinical applications, there are nearly half of breast cancer patients are insensitive to TM. Therefore, the development of resistance to TM is an important issue in the treatment of breast cancer. Sulforaphane (SFN) is a compound derived from cruciferous plants and many studies have been demonstrated that SFN possesses anticancer potential and sensitizes cancer cells to chemotherapies. In this study, SFN was examined for its cytotoxic effect against an estrogen receptor positive breast cell line MCF-7 and a triple-negative (estrogen receptor, progesterone receptor, and HER2 negative) breast cancer (TNBC) cell line MDA-MB-468. Our results have demonstrated that SFN dose-dependently inhibited the cell viability of MDA-MB-468 and MCF-7 cells. In these two breast cancer cell lines, SFN significantly influenced the phosphorylation of PDK1, AKT, mTOR, S6K, and S6. In addition, a low concentration of SFN in combination with tamoxifen enhanced the cytotoxicity of the latter and significantly inhibited the phosphorylation of AKT, mTOR, S6K, and S6. Taken together, our results indicate that SFN can inhibit AKT/mTOR/S6K pathway and lead to cancer cell apoptosis. Furthermore, SFN can sensitize breast cancer cells to TM treatment through inhibition of AKT/mTOR/S6K pathway.

縮寫表 4
摘要 6
Abstract 7
第一章 緒論 9
一、 乳癌 10
二、 AKT/mTOR/S6K之訊息路徑 16
三、 細胞凋亡路徑 23
四、 Sulforaphane (SFN) 26
五、 Tamoxifen (TM) 30
六、 研究動機及目的 33
第二章 實驗材料與方法 35
一、實驗材料 36
二、實驗方法 39
第三章 實驗結果 46
SFN抑制MDA-MB-468和MCF-7的細胞存活率 47
SFN對於AKT及PDK1活化之影響 47
SFN對於AKT下游調控因子之影響 48
SFN對於細胞凋亡重要因子caspase之影響 49
比較mTOR抑制劑、PDK1抑制劑及SFN對AKT/mTOR/S6K路徑之影響 49
SFN可以增強TM的細胞毒殺作用 51
低濃度SFN合併TM對於AKT活化之影響 51
低濃度SFN合併TM對於AKT下游調控因子之影響 52
低濃度SFN合併TM對於細胞凋亡因子caspase和PARP之影響 52
第四章 圖表 54
第五章 綜合討論與未來展望 66
第六章 參考文獻 72


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