臺灣博碩士論文加值系統

樟芝（Antraodia cinnamomea）為台灣特有之真菌類，非常稀少且珍貴，主要原因為其只生長在中高海拔之牛樟樹上且其子實體生長非常緩慢，難以人工培養。在傳統上，主要用於治療腹瀉、高血壓及肝癌等，另已有研究指出樟芝子實體具有抗癌及抗氧化活性。但由於子實體過於昂貴，且目前研究指出液態培養之樟芝菌絲體及發酵濾液具有抗癌、保肝、抗氧化、抗發炎與神經保護等作用，所以目前以發展液態培養之樟芝來取代其子實體之用途。此外，由於目前肺癌及肝癌為分別國人惡性腫瘤之第一、二位，因此本研究乃探討深層培養之樟芝菌絲體乙醇萃取物（ethanolic extract of mycelia of A. cinnamomea，EMA）處理人類肺癌（A549）及肝癌（SK Hep-1及HA 22T/VGH）細胞生長影響及其作用機轉。結果顯示，EMA可抑制A549、SK Hep-1（p53-positve）及 HA 22T/VGH（p53-deletion，HBsAg [+]）細胞生長，其在處理48小時後，IC50分別為30.9、48.2及117.1 μg/ml。進一步以流式細胞儀分析EMA對於此三株細胞生長之抑制情形，結果顯示細胞週期分別停滯於S期（A549，40 μg/ml）、G0/G1期（SK Hep-1，20 μg/ml）及S期（HA 22T/VGH，160 μg/ml）。此外，以EMA處理A549 （80 μg/ml）、SK Hep-1 （80 μg/ml）及 HA 22T/VGH（160 μg/ml）24小時後，細胞皆進行細胞凋亡（apoptosis）（sub G1期增加）， DNA電泳結果也顯示DNA呈現片段化（DNA ladder）。此外，結果顯示EMA誘導此三株細胞進行細胞凋亡可能是與caspase-3的表現及活化有關。

Antraodia cinnamomea is well-known as a traditional Chinese medicine in Taiwan. Because the growth rate of the natural A. cinnamomea in the wild is very slow, it is difficult to be cultured in green house. It is very expensive to obtain to fruiting bodies. Additionally, it might be a possible and economical way to utilise the submerged fermentation to produce the product of A. cinnamonea with stronger bioactivity. Previous researches have shown A. cinnamomea has many biological activities, such as anti-cancer activity, hepatoprotection, anti-oxidation, anti-inflammation, neuroprotection, and so on. In addition, lung and liver cancer are very common malignant tumors in Taiwan. This study was to investigate the effect of ethanolic extract of mycelia of A. cinnamomea (EMA) in submerged fermentation on the human lung (A549) and liver (SK Hep-1 and HA 22T/VGH) cancer cell lines and their possible mechanisms. The results showed that EMA inhibit the cell viability of A549, SK Hep-1 (p53-positive) and HA 22T/VGH (p53-deletion, HBsAg [+]) for 48hr, and their IC50 value were 30.9、48.2 and 117.1 μg/ml, respectively. The results of cell cycle analysis showed that EMA induced cell cycle arrest in S (A549, 40 μg/ml), G0/G1 (SK Hep-1, 20 μg/ml) and S (HA 22T/VGH, 160 μg/ml) phase. Furthermore, EMA could induce apoptosis (accumulation of sub G1 phase) in A549 (80 μg/ml), SK Hep-1 (80 μg/ml) and HA 22T/VGH (160 μg/ml), and the DNA ladder were presented in these three cell lines by DNA electrophoresis. By fluorescence microscope, results indicate EMA induced A549, SK Hep-1 and HA 22T/VGH apoptosis through induction of caspases-3 and expression caspase-3.

目錄
摘要 I
Abstract II
目錄 III
表次 V
圖次 VI
壹、 前言 1
貳、 文獻回顧 4
一、 癌症 4
（一）癌症 4
（二）肝癌簡介 5
（三）肺癌簡介 10
二、 實驗用材料-樟芝 14
（一）樟芝之簡介 14
（二）成分分析 15
（三）樟芝之保健功效 21
三、 細胞週期、細胞凋亡與細胞壞死 24
（一）細胞週期（cell cycle） 24
（二）細胞凋亡的機轉 31
參、 研究目的與實驗架構 38
一、 研究目的 38
二、 實驗架構 40
肆、 實驗材料與方法 41
一、 實驗材料 41
二、 實驗細胞株 41
（一）人類肺癌細胞株A549 41
（二）人類肝癌細胞株SK Hep-1 41
（三）人類肝癌細胞株HA 22T/VGH 41
三、 化學藥品與溶劑 41
四、 儀器設備 44
（一）樣品前處理與萃取用儀器 44
（二）細胞培養用儀器 44
（三）樣品分析用儀器 45
五、 實驗方法 46
（一）樣品之前處理與製備 46
（二）細胞培養 46
（三）細胞存活率分析-MTT assay 48
（四）細胞形態觀察 49
（五）細胞週期分析 49
（六）DNA片段化測定 49
（七）Caspase-3活性之分析 50
（八）西方墨點法-Western blot assay 51
六、 統計分析 55
伍、 結果 56
一、 樟芝菌絲體乙醇萃取物（EMA）對人類肺癌細胞株A549影響 56
（一）細胞存活率之影響 56
（二）細胞形態之影響 56
（三）細胞週期之影響 56
（四）DNA片段化的影響 57
（五）Caspase-3活性的影響 58
二、 樟芝菌絲體乙醇萃取物（EMA）對人類肝癌細胞株SK Hep-1影響 58
（一）細胞存活率之影響 58
（二）細胞形態之影響 59
（三）細胞週期之影響 59
（四）DNA片段化的影響 60
（五）Caspase-3活性的影響 60
三、 樟芝菌絲體乙醇萃取物（EMA）對人類肝癌細胞株HA 22T/VGH影響 60
（一）細胞存活率影響 60
（二）細胞形態之影響 61
（三）細胞週期之影響 61
（五）Caspase-3活性的影響 62
陸、 討論 63
柒、 結論 67
捌、 圖表 68
玖、 參考文獻 86
附錄 95

表次
表一 台灣地區主要死因（行政院衛生署94年） 3
表二 B型肝炎與肝癌之相關原因 9
表三 實驗細胞株之特性 13
表四 細胞週期調控因子 26
表五 不同型式之細胞死亡的特徵 33
表六 細胞壞死與細胞凋亡之比較。 33
表七 A549以樟芝菌絲體乙醇萃出物處理24小時後對其細胞週期之影響 70
表八 SK Hep-1以樟芝菌絲體乙醇萃出物處理24小時後對其細胞週期之影響 76
表九 HA 22T/VGH以樟芝菌絲體乙醇萃出物處理24小時後對其細胞週期之影響 82

圖次
圖一 台灣地區主要癌症死因百分率（行政院衛生署94年） 3
圖二 從樟芝子實體萃取物中發現之三萜類化合物之化學結構 18
圖三 細胞週期及其相關調控分子。 28
圖四 細胞凋亡之兩個主要路徑。 34
圖五 死亡受體路徑。 36
圖六 死亡受體路徑。 37
圖七 樟芝菌絲體乙醇萃出物之濃度與作用時間對A549細胞存活率之影響 68
圖八 不同濃度之樟芝菌絲體乙醇萃出物對A549細胞形態之影響 69
圖九 樟芝菌絲體乙醇萃出物對A549細胞週期之影響 70
圖十 A549經樟芝菌絲體乙醇萃出物處理後DNA片段化的影響 71
圖十一 樟芝菌絲體乙醇萃出物對A549細胞內caspase-3活性的影響 72
圖十二 樟芝菌絲體乙醇萃出物對A549細胞內caspase-3表現量的影響 73
圖十三 樟芝菌絲體乙醇萃出物之濃度與作用時間對SK Hep-1細胞存活率之響 74
圖十四 不同濃度之樟芝菌絲體乙醇萃出物對SK Hep-1細胞形態之影響 75
圖十五 樟芝菌絲體乙醇萃出物對SK Hep-1細胞週期之影響 76
圖十六 SK Hep-1經樟芝菌絲體乙醇萃出物處理後DNA片段化的影響 77
圖十七 樟芝菌絲體乙醇萃出物對SK Hep-1細胞內caspase-3活性的影響 78
圖十八 樟芝菌絲體乙醇萃出物對SK Hep-1細胞內caspase-3表現量的影響 79
圖十九 樟芝菌絲體乙醇萃出物之濃度與作用時間對HA 22T/VGH細胞存活率之影響 80
圖二十 不同濃度之樟芝菌絲體乙醇萃出物對HA 22T/VGH細胞形態之影響 81
圖二十一 樟芝菌絲體乙醇萃出物對HA 22T/VGH細胞週期之影響 82
圖二十二 HA 22T/VGH經樟芝菌絲體乙醇萃出物處理後DNA片段化的影響 83
圖二十三 樟芝菌絲體乙醇萃出物對 HA 22T/VGH細胞內caspase-3活性的影響 84
圖二十四 樟芝菌絲體乙醇萃出物對HA 22T/VGH細胞內caspase-3表現量的影響 85

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