臺灣博碩士論文加值系統

近年來，肺癌在世界各地包含台灣，是個常見且發生率很高的惡性腫瘤，同時也是死亡人數第一名的癌症，五年的存活率更是小於15%。因此，預防癌症的發生率更顯得格外的重要。蔬菜及水果含豐富的多酚物質具有抗氧化及清除自由基、與誘導癌症細胞產生凋亡和有效的抑制癌症細胞的生長的功能。
本研究探討以富含多酚的荔枝萃取物與芒果核仁萃取物處理非小細胞肺癌細胞株包含肺腺癌(A549)以及肺大細胞癌(NCI-H661)後偵測細胞生長特性與細胞內機制以及相關的蛋白表現，以探討這兩個萃取物對非小細胞肺癌的抑制功效與所涉及的可能機制。LCSE含總多酚每克乾重約400毫克，且對兩株肺癌細胞株生長皆有顯著的抑制效果，其細胞機制為細胞週期停滯G1或G2/M期與誘導粒線體媒介的細胞凋亡。MGSE對兩株肺癌細胞生長均有生長抑制作用，其細胞機制來自於誘導粒線體媒介的細胞凋亡或細胞週期停滯S或G1期。
西方墨點法結果表明，荔枝籽多酚在這兩株細胞株的G2/M期停滯來自於cyclin B的蛋白表現量減少。在細胞凋亡可看到PARP斷裂、cleaved PARP上升，casepase 3 、9的活化。而我們將探討酪胺酸激酶受體的意義，特別是分子機制的響應，而我們也發現荔枝籽萃取物亦可抑制表皮生長因子接受器(EGFR)的活化。而在芒果籽多酚對兩株細胞的細胞週期S phase的停滯來自於cyclin A的蛋白表現量減少，且casepase 3的活化與PARP斷裂誘導細胞凋亡。
LCSE與MGSE皆可抑制肺癌不同細胞株的生長，荔枝多酚抑制生長的主要機制來自於造成細胞週期阻滯和誘導細胞凋亡以及抑制表皮生長因子的機制而芒果多酚主要是來自於細胞週期的停滯。荔枝籽萃取物對肺癌細胞株的EGFR和其在訊號傳遞的相關蛋白表現。因此，LCSE與MGSE在未來可望作為新型功能性食品或肺癌預防劑開發的潛力。

Background：
Lung cancer,arising in the develoed countries including Taiwan, is a highly morbidity and morbidity malignant tumor with less than 15% five-year survival rate. Therefore, the preventive and treatment trategies for this cancer is particularly important. Vegetables and fruits, rich in polyphenols (such as: green tea, red wine, grapes),possesses free radical scavenge and inducing effect on cancer cell apoptosis. So far, it has not yet fully understood the effect of litchi seed or Mango kernel extracts on lung cancer. This thesis is mainly aim at evaluating the possible application of litchi seed extract (LCSE) and mango kernel extract (MGSE) against lung cancer.
Results：
This thesis examines the cellular and molecular changes of lung cancer A549 and NCI-H661 cells after treatment with the different concentration of LCSE and MGSE. LCSE contains about 400mg of total polyphenol which is calibrated by gallic acid using Folin solution and measured by colorimetric method. LCSE represented the inhibitory effect of the growth on lung cancer cell lines.The cellular mechanisms were mitochondria- mediated apoptosis and the induction of cell cycle arest for the G1 and G2 / M phase. MGSE induced growth of two lung cancer cell growth inhibition the cellular mechanisms of mitochondrial medium induced apoptosis or cell cycle arrest in S phase.
Western blot results showed that the LCSE reduced protein expression from the cyclin B, with G2 / M arrest in the two cell lines. PARP cleavage rised which represented the activation of casepase 3. Furthermore,we investigated the association of the tyrosine kinase receptor. In particular, the response of molecular mechanism, we also found that LCSE may also inhibit the activation of epidermal growth factor receptor (EGFR) and its downstream signaling. MGSE arrested two cells at G1phase and S phase of cell cycle, which was associated with the reduction of cyclin A expression, and casepase 3 activation and cleaved PARP induction of apoptosis.
LCSE and MGSE can be inhibited lung cancer cell lines growth, LCSE inhibit the growth of the main mechanism from the mechanism causing cell cycle arrest and induction of apoptosis and inhibition of epidermal growth factor and MGSE mainly from the cell cycle arrest. The litchi seed extract on lung cancer cell lines with EGFR signaling protein expression. Therefore, LCSE and MGSE in the future we can expect as a new functional food or the potential for lung cancer prevention agent development.

致 謝 I
摘要 II
ABSTRACT IV
目錄 VI
表目 X
圖目錄 XI
第一章 緒論 1
1.1 前言 1
1.2 荔枝籽多酚( LITCHI SEED EXCACTS, LCSE ) 2
1.2芒果(MANGO) 7
1.3多酚與癌症 11
1.4自由基與癌症 11
1.5肺癌(LUNG CANCER) 12
1.6表皮生長因子受體 22
1.7細胞週期 26
1.8細胞凋亡 29
1.9動物實驗 32
1.10 研究設計與目的 33
第二章 研究材料與方法 34
2.1實驗架構流程 34
2.1.1荔枝籽多酚萃取物 34
2.1.2芒果籽多酚萃取物 35
2.2 實驗樣本 36
2.2.1荔枝籽 36
2.2.2芒果籽 36
2.3 荔枝籽之萃取 36
2.3.1 荔枝籽前處理 36
2.3.2 乙醇浸泡萃取法 36
2.4 芒果籽之萃取 37
2.4.1芒果籽前處理 37
2.4.2 乙醇浸泡萃取法 37
2.5成份分析 37
2.5.1 總酚類化合物(Total polyphenols)含量測定 37
2.5.2 總類黃酮（Total flavonoids）含量測定 38
2.5.3 縮合型單寧（Condensed tannin）含量測定 38
2.6癌細胞特性實驗 38
2.6.1實驗用細胞株 38
2.6.2解凍細胞 39
2.6.3細胞株繼代培養 40
2.6.4細胞存活率分析 40
2.6.5細胞群落形成分析(Cell colony formation assay) 42
2.6.6細胞週期分析(Cell cycle analysis) 42
2.6.7細胞凋零試驗(Apoptosis Assays) 43
2.6.8 粒線體膜電位分析(Rhodamine 123 assays) 44
2.7 免疫染漬法 45
2.7.1 細胞蛋白萃取 45
2.7.2 蛋白質濃度測定 45
2.7.3 SDS-聚丙烯醯胺膠體電泳(SDS-Polyacryamide Gel Electrophoresis) 46
2.7.4 蛋白質轉漬 48
2.7.5 免疫墨點法(Immunobloting) 48
2.8 統計分析 50
2.9動物實驗 50
2.9.1實驗樣本 50
2.9.2實驗用小鼠品系 51
2.7.3餵食小鼠 51
2.7.4 解剖小鼠 52
2.7.5 小鼠血液檢查 52
2.7.6小鼠血清生化標記檢查 52
2.7.7小鼠組織包埋 53
2.7.8小鼠組織染色 53
第三章結果與討論 55
3.1種籽萃取物之多酚種類成分分析 55
3.1.1總酚類化合物（Total phenolics） 55
3.1.2總類黃酮（Total flavonoids） 56
3.1.3縮合單寧（Condensed tannin） 56
3.2荔枝籽萃取物對非小細胞肺癌細胞株之生長抑制集相關分子機制 57
3.2.1荔枝籽萃取物(LCSE)對肺臟細胞存活率分析 57
3.2.2荔枝籽萃取物(LCSE)對非小細胞肺癌的群落生成能力之影響 58
3.2.3荔枝籽萃取物(LCSE)對非小細胞肺癌之細胞週期分析 58
3.2.4荔枝籽萃取物(LCSE)對非小細胞肺癌之細胞週期相關蛋白之影響 59
3.2.5荔枝籽萃取物(LCSE)對非小細胞肺癌之細胞凋零分析 60
3.2.7荔枝籽萃取物(LCSE)對非小細胞肺癌之細胞凋零相關蛋白之影響 61
3.2.8荔枝籽萃取物(LCSE)誘導非小細胞肺癌的表皮生長因子之蛋白質表 62
3.3芒果籽萃取物對非小細胞肺癌細胞株之生長抑制集相關分子機制 63
3.3.1芒果籽萃取物(MGSE)對非小細胞肺癌存活率分析 63
3.3.2芒果籽萃取物(MGSE)對非小細胞肺癌的群落生成能力之影響 64
3.3.3芒果籽萃取物(MGSE)對非小細胞肺癌之細胞週期分析 64
3.3.4芒果籽萃取物(MGSE)對非小細胞肺癌之細胞週期相關蛋白之影響 65
3.3.5芒果籽萃取物(MGSE)對非小細胞肺癌凋零之分析 65
3.3.6芒果籽萃取物(MGSE)對非小細胞肺癌之細胞凋零相關蛋白之影響 66
第四章 結論 88
4.1荔枝籽對非小細胞肺癌之抑制 88
4.2芒果籽對非小細胞肺癌之抑制 89
第五章 參考文獻 91
一、中文摘要 91
二、英文摘要 91

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