臺灣博碩士論文加值系統

Tawanofungus camphoratus俗名稱為牛樟芝，為台灣特有的藥用真菌。本研究之目的為探討固態栽培樟芝酒精粗萃物中具有癌症逆轉(Cancer reversion)的特性並能抑制腫瘤細胞生長，再結合分子造影系統(Molecular imaging system)，即時觀察生物活體內細胞分子層次之變化。分別以人類肺癌細胞(H441GL cells)及子宮頸癌細胞(HeLa cells)作為篩選分析之細胞株。首先，以固態栽培樟芝酒精粗萃物作用於人類肺癌細胞及子宮頸癌細48小時，初步得到其IC50分別為100?慊/mL及300 ?慊/mL，樟芝酒精粗萃物具有明顯抑制腫瘤細胞生長能力。第一部份實驗分析樟芝酒精粗萃物調控H441GL肺癌細胞之反應，結果顯示可使H441GL肺癌細胞週期停滯於G0/G1時期，並隨著劑量增加而抑制H441GL肺癌細胞之遷移性(Cell migration)，但對細胞毒殺不走凋亡路徑(Apoptosis)，而是走壞死路徑(Necrosis)。在動物實驗方面，每三天餵食500?慊樟芝酒精粗萃物的確具有抑制H441GL肺癌腫瘤生長之效果。第二部份實驗，樟芝酒精粗萃物亦能抑制HeLa子宮頸癌細胞內鹼性磷酸酵素(Alkaline phosphates)表現，並具有癌症逆轉之特性，抑制E7致癌蛋白和提升p53、pRB抑癌基因表現。研究顯示樟芝酒精粗萃物對肺癌細胞株(H441GL cell/p53 mutant)和子宮頸癌細胞株(HeLa cell/p53 wild type)之p53蛋白表現量無顯著影響，顯示樟芝之酒精粗萃物在調控p53蛋白作用機轉中無明顯之影響能力，於動物實驗中樟芝確實具有抑制HeLa子宮頸癌腫瘤細胞生長之效果，故應用分子造影能提供快速與有效地評估樟芝酒精萃物之抑制腫瘤療效。

The fruiting body of Taiwanofungus camphoratus is well known in Taiwan as
“niu-chang chih” or “jang-jy”. The objective of this research is to identify the bioactive compounds in Taiwanofungus camphoratus’s ethanol extract from solid-state growen with cancer reversion and anti-tumor activities. This non-invasive molecular imaging is useful in assessing tumor volume in vivo. By treating H441GL cells ( human non-small lungs cancer cells ) and HeLa cells ( human cervical cancer cells ) with ethanol extracts of Taiwanofungus camphoratus for 48 hrs. The ethanol extract was found to possess the highest anti-tumor activities with the IC50 values of 100?慊/ml and 300 ?慊/ml, respectively. Data from flow cytometry analysis indicated that Taiwanofungus camphoratus-mediated antiproliferation effect related to G0/G1 phase arrest on H441 cells. Moreover, this Taiwanofungus camphoratus –induced G0/G1 cell cycle arrest was associated with decrease the expression levels of cyclin A and increase in cyclin D2、cyclinE proteins . Dose-dependent treatment of H441GL cells with Taiwanofungus camphorate resulted in the inhibition of cell migration and commitment to cell necrosis. Taiwanofungus camphoratus induced tumorigenic HeLa cells to revert back to a normal-like phenotypic state (cancer reversion), such as the loss of alkaline phosphatase expression. This reversion was associated with the down- regulation of E7 oncoproteins and subsequent reactivation of p53/pRB gene. In vivo animal tumorigenicity studies were demonstrated that Taiwanofungus camphorates was effective inhibited tumor grow. These results suggest that Taiwanofungus camphorates may be used as a potent agent for cancer therapy.

中文摘要 I
Abstract II
第一章 緒論
第一節 前言 1
第二節 腫瘤形成機制 3
第三節 肺癌(Lung cancer) 4
第四節 子宮頸癌(Cervical cancer) 6
第五節 牛樟芝 10
第六節 癌症逆轉機制 14
第七節 子宮頸癌細胞逆轉之研究 15
第八節 分子造影 16
第九節 研究架構 18
第貳章 實驗材料與方法
第一節 藥品與試劑 21
第二節 細胞株與動物 24
第三節 細胞培養 24
第四節 樟芝製備 25
第五節 薄層色層分析法(Thin layer chromatography;TLC) 25
第六節 細胞存活率試驗( MTT assay ) 25
第七節 細胞群落生成率試驗 (Cell colony-forming assay) 26
第八節 鹼性磷酸酵素分析試驗(Alkaline phosphates assay) 27
第九節 腫瘤細胞回復率試驗(Reversion frequency) 27
第十節 細胞週期分析試驗( Cell cycle assay) 27
第十一節 細胞死亡分析試驗( Cell death assay) 28


第十二節 細胞遷移測定(Wound scratch assay) 29
第十三節 反轉錄聚合酶連鎖反應(RT-PCR) 29
第十四節 西方點墨法(Western blot) 31
第十五節 洋菜膠配法(Agarose gel preparation) 34
第十六節 勝任菌體之製備(Competent bacterial cells) 35
第十七節 轉形作用(Transformation) 35
第十八節 小量質體製備 35
第十九節 轉染作用(Transfection) 36
第二十節 細胞冷光酵素微盤分析 36
第二十一節 動物實驗 37
第二十二節 非侵入式活體動物生物冷光造影 38
第參章 結果
第一節 樟芝粗萃物分析與細胞存活率試驗
A. 酒精物和水粗萃物製備 39
B. 薄層色層分析法 39
C. 酒精粗萃物和水粗萃物對細胞存活率之影響 39
第二節 樟芝酒精粗萃物對H441GL肺癌細胞生理活性影響
A. 樟芝酒精粗萃取物對H441GL肺癌細胞存活率之影響 40
B. 樟芝酒精粗萃取物對H441GL肺癌細胞死亡分析 40
C. 樟芝酒精粗萃取物對H441GL肺癌細胞週期影響 41
D. 樟芝酒精粗萃取物對H441GL肺癌細胞遷移之影響 41
E. H441GL肺癌細胞In vitro生物冷光活性分析 42
F. 樟芝酒精粗萃取物治療H441GL肺癌動物模式 42
第三節 樟芝酒精粗萃液對HeLa子宮頸癌細胞生理活性影響
A. 樟芝酒精萃取物對HeLa子宮頸癌細胞存活率之影響 43
B. 樟芝酒精萃取物對HeLa子宮頸癌細胞鹼性磷酸酶之影響 44
C. 樟芝酒精萃取物對HeLa子宮頸癌細胞瘤細胞回復率之分析 45
D. 樟芝酒精粗萃取物對HeLa子宮頸癌細胞週期影響 45
E. 樟芝酒精粗萃取物對CGL1類正常細胞基因與蛋白質之影響 45
F. 樟芝酒精粗萃取物對HeLa子宮頸癌基因與蛋白質之影響 45
G. HeLa/RL子宮頸癌細胞In vitro生物冷光活性分析 46
H. 樟芝酒精粗萃取物治療HeLa/RL子宮頸癌動物模式 46
第肆章 討論 47
第伍章 結論 52
第陸章 參考文獻 53


圖表與附錄
圖一、樟芝酒精粗萃物和水粗萃物製備流程圖 63
圖二、薄層色層分析法 64
圖三、細胞存活率試驗 65
圖四、樟芝酒精粗萃物與水粗萃物對細胞存活率之影響試驗 66
圖五、H441GL肺癌細胞培養於不同濃度樟芝酒精粗萃物 67
圖六、樟芝酒精粗萃物對肺癌細胞存活率影響之試驗 68
圖七、H441GL群落生成實驗 69
圖八、H441GL肺癌細胞死亡試驗 70
圖九、H441GL肺癌細胞週期試驗 71
圖十、樟芝影響H441GL細胞cyclin細胞週期調控蛋白之表現 72
圖十一、樟芝影響H441GL細胞CXCR4基因表現 73
圖十二、H441GL肺癌細胞遷移測定 74
圖十三、H441GL細胞冷光酵素測定 75
圖十四、H441GL肺癌動物腫瘤生長趨勢線圖(測微尺法) 76
圖十五、H441GL肺癌動物實驗分子造影圖 77
圖十六、H441GL肺癌動物實腫瘤生長趨勢線圖(分子造影量化法) 78
圖十七、CGL1類正常細胞培養 79
圖十八、HeLa子宮頸癌細胞培養 80
圖十九、樟芝酒精粗萃物對細胞存活率影響之試驗 81
圖二十、群落生成實驗 82
圖二十一、鹼性磷酸酵素分析 83
圖二十二、腫瘤細胞回復分析 84
圖二十三、HeLa子宮頸癌細胞週期試驗 85
圖二十四、樟芝對CGL1和HeLa細胞p53；RB；E6；E7基因之影響 86
圖二十五、樟芝對CGL1和HeLa細胞p53；p21和E7之影響 87
圖二十六、HeLa/RL細胞冷光酵素測定 88
圖二十七、HeLa/RL動物實驗老鼠腫瘤生長趨勢線圖(測微尺法) 89
表一、H441GL群落生成實驗 90
表二、CGL1群落生成實驗 90
表三、HeLa群落生成實驗 90
附錄一、行政院衛生署統計國人95年度十大主要死因 91
附錄二、行政院衛生署統計95年度前十大主要癌症順位 91
附錄三、子宮頸癌致癌原理 92
附錄四、細胞週期 92
附錄五、珊瑚蟲冷光酵素與其受質(coelenterazine)作用原理 93
附錄六、螢火蟲冷光酵素與其受質(D-Luciferin)作用原理 93

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