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研究生:張力中
研究生(外文):Li-Chung Chang
論文名稱:牛樟芝子實體純化物antcin A在肝癌異種移植模型中誘導腫瘤細胞凋亡機制探討
論文名稱(外文):Antcin A purified from Antrodia cinnamomea's fruiting body induced apoptosis in xenograft models of hepatocellular carcinoma
指導教授:吳宗正吳宗正引用關係
指導教授(外文):Tzong-Zeng Wu
學位類別:碩士
校院名稱:國立東華大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
論文頁數:100
中文關鍵詞:肝癌牛樟芝動物細胞凋亡
外文關鍵詞:antrodia cinnamomeaantcin AHepG2apoptosis
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  • 收藏至我的研究室書目清單書目收藏:1
肝癌於行政院衛生署在民國101年統計位居十大癌症死亡第二位。由於肝癌在初期的時候症狀不明顯,所以發現罹患肝癌時幾乎是肝癌末期。手術切除是主要的治療方式,但術後肝癌的復發率在五年內仍高達七成。術後搭配藥物能稍微降低復發率,但是卻有許多副作用。因此,尋找到能夠抑制肝癌又沒太大副作用的藥物成為重要的研究課題。牛樟芝為台灣特有的真菌,含許多生理活性成分,具有治療肝病療效。近期有許多相關研究指出牛樟芝子實體具有良好的抗癌效果。本實驗室先前研究證實牛樟芝子實體純化物antcin A 在體外(in vitro)實驗中能夠抑制肝癌細胞 HepG2 生長,並且誘導它走向凋亡,並對人類正常細胞株CCD-966SK沒有毒殺性。本研究是以HepG2異種移植之動物模型探討 antcin A 抑制肝腫瘤能力 ,並探討在活體內其作用機制。細胞存活率測試結果顯示,antcin A能抑制HepG2生長,IC50約 25 μg/ml。以不同濃度antcin A (1, 5, 30 mg/kg)在HepG2異種移植模型中處理2週,腫瘤體積與重量隨antcin A濃度增加而減少,顯示antcin A具有抑制腫瘤生長能力。在H&E染色與免疫組織化學染色實驗中觀察到antcin A促使HepG2腫瘤有絲分裂細胞與Ki67表現減少。在TUNEL assay 實驗中顯示antcin A使HepG2腫瘤細胞產生DNA片段化,證實antcin A會誘導HepG2腫瘤凋亡。經Western blotting結果證實antcin A會促使TRAIL/DR5、FasL/Fas蛋白複合體形成而促使下游caspase-8,並促使Bid活化成tBid,造成Bax與Bad表現量上升、Bcl-xL表現下降而促使cytochrome C被釋出並活化caspase-9,進一步活化下游之caspase-3,切割PARP而抑制DNA修復,促使腫瘤細胞走向凋亡。此外IGF1、IGF1R、AKT與p-AKT的表現量下降,證實antcin A亦經由IGF1與IGF1R訊息傳遞路徑抑制HepG2腫瘤生長並誘導凋亡。與市售抗癌藥物結合測試結果顯示,結合處理對HepG2腫瘤生長抑制效果比單獨處理抗癌藥物明顯。基於以上結果,antcin A有機會進一步發展成新的抗肝癌藥物或化療增敏劑。
Hepatocellular carcinoma (HCC) is the fifth most common malignancies and the second leading cause of cancer-related mortality in Taiwan. Owing to the symptoms of HCC were not obvious in the early stages, so when the tumor had been detected almost in the hepatoma terminal stage. Currently, surgical resection is the main treatment, but the recurrence rate of HCC is still over 70% in five years. Although after surgery with chemotherapy drugs can slightly reduce the relapse rate, but there are many side effects. Therefore, the searching of new drug that can inhibit liver cancer without any side effects or with significant reduction side effects become an important research topic. Antrodia cinnamomea (AC) is an unique fungus in Taiwan which contains a large number of physiologically active compounds and has efficacy in liver disease. There were a lot of studies indicated that the Antrodia cinnamomea’s fruiting bodies (ACFB) had remarkable good anti-cancer activity. Our previous study demonstrated that antcin A purified from ACFB could significantly inhibit the growth of HepG2 cells and induced cell apoptosis in vitro. Especially valuable was antcin A did not harm to normal human cell line CCD-966 SK cells. The purpose of this study was to investigate the capability of antcin A inhibition of hepatic tumors in animal models of HepG2 xenografts and to elucidate the mechanism of its action. The results of viability assay showed that antcin A treatment could significantly inhibit the growth of HepG2 cells and the effective dose (IC50) were approximately 25 μg/ml. HepG2 tumor were treated with antcin A (1, 5, 30 mg/kg ) in xenograft animal model. The tumor growth was inhibited by antcin A in a dose-dependent manner as indicated by the decrease in tumor volume and tumor weight after 2 weeks of treatment. H&E and immunohistochemistry stain showed that antcin A promoted the decrease of HepG2 tumor mitotic cells and Ki67 expression. TUNEL assay showed that antcin A treatment resulting in DNA fragmentation within HepG2 tumor tissue and this evidence confirmed that antcin A could induce HepG2 tumor apoptosis. Western blotting showed that antcin A activated the TRAIL/DR5 and FasL/Fas apoptosis pathways. The activation of TRAIL/DR5 and FasL/Fas by antcin A induced caspase-8 activation. Caspase-8 activated tBid, and then tBid further stimulated with the increase of Bax and Bad, and the decrease of Bcl-xL. As Bcl-2 family inactivated, cytochrome c released from mitochondria to cytoplasm and further downstream activated caspase-9. Caspase-9 activated caspase-3 and PARP were cleaved, and then induced HepG2 tumor apoptosis. In addition, from the results of decreasing in the expression of IGF1, IGF1R, AKT and p-AKT, we suggested that antcin A could down-regulated IGF1/IGF1R signaling pathway and induced apoptosis. Furthermore, antcin A combined with Sunitinib, a commercially available anti-cancer drug, and test results showed that the effect of suppressing tumor growth by using combined treatments were significantly more than individual Sunitinib. Based on the above results, antcin A might have a great potential to further develop into a new anticancer drug or chemo-sensitizer for liver cancer therapy.

中文摘要 I
Abstract III
目錄 V
表目錄 XI
圖目錄 XIII
第一章 前言 1
第二章 文獻回顧 3
一、 牛樟芝簡介( Antrodia cinnamomea) 3
1. 生長特徵 3
2. 分類法 3
3. 牛樟芝功效 4
4. 活性成分 5
4.1 抗發炎 10
4.2 抗氧化 10
4.3 保護肝臟 10
4.4 增強皮膚修復 11
4.4 抗腫瘤 11
二、 肝癌介紹 13
1. 肝癌之死亡率排行 13
2. 肝臟 13
3. 肝硬化 14
4. 肝癌 14
5. 危險因子 15
6. 肝癌治療方式 15
三、細胞凋亡 18
1. 細胞死亡形式與形態學特徵 18
2. 細胞凋亡之訊息傳遞路徑 19
第三章、研究目的 21
第四章、實驗架構 23
第五章、材料與方法 25
一、牛樟芝樣品粗萃取 25
1. 牛樟芝子實體粗萃取 25
2. 管柱層析法 25
3. 半製備HPLC分離法 26
4. HPLC分析 26
二、人類肝癌細胞株HepG2培養 27
1. DMEM細胞培養液配置 27
2. 冷凍細胞解凍及活化 27
3. 肝癌細胞培養 27
4. 細胞繼代及分盤 28
三、細胞存活率測試( MTT assay) 29
四、動物實驗 29
1. 第一次動物實驗 29
2. 第二次動物實驗 30
五、組織切片染色 31
1. H &E染色 31
2. 細胞凋亡測試( TUNEL assay ) 32
3. 免疫組織化學染色(Immunohistochemistry) 32
六、西方墨點法 33
1. 蛋白質萃取 33
2. 蛋白質定量 33
3. 蛋白質電泳及轉漬 34
4. 蛋白質免疫呈色 34
七、統計分析 34
第六章、實驗結果 37
一、 牛樟芝子實體之萃取與純化 37
1. 牛樟芝子實體萃取 37
2. 管柱層析 37
3. 半製備HPLC純化Antcin A 37
二、細胞存活率測試 ( MTT assay) 38
1. 乙醇溶劑對HepG2細胞株之存活率影響 38
2. 牛樟芝子實體粗萃物(ACCE)對HepG2細胞株之存活率影響………………………………………………………………38
3. 半製備HPLC純化分離之antcin A對HepG2細胞株存活率影響 38
4.市售藥Doxorubicin、Mitoxantrone、Docetoxel與5-FU對HepG2細胞株之存活率影響 39
三、動物實驗 39
1. 市售抗癌藥物Doxorubicin、Mitoxantrone對NOD-SCID小鼠毒性測試 39
2. Antcin A對HepG2異種皮移植動物模型腫瘤表現之影響 …………………………………………………………….40
3. 市售抗癌藥物sunitibin結合antcin A對HepG2異種皮移植動物模型腫瘤表現之影響 40
四、組織切片染色 41
1. H&E 染色 41
2. Ki67蛋白表現 41
3. TUNEL 42
4.Western blot 42
第七章、討論 75
第八章、結論 83
第九章、未來展望 85
第十章、參考文獻 87




















表目錄
表1、民國101年度十大癌症死因統計表(行政院衛生署) 13
表 2、腫瘤體積、體重比較值。T:treatment;C:control 55
表 3、腫瘤體積、體重比較值。T:treatment;C:control 58













圖目錄
圖1、牛樟芝經分離所得倍半萜(Sesquiterpenoids)及雙萜化合(diterpenoids) 6
圖2、牛樟芝經分離所得麥角甾烷型三萜類化合物(ergostane type triterpenoids) 6
圖3、牛樟芝經分離所得羊毛甾烷(lanostane) 型三萜類化合物(ergostane type triterpenoids) 7
圖4、牛樟芝經分離所得三萜類化合物(triterpenoids) 7
圖5、牛樟芝經分離所得苯環化合物(benzenoids) 8
圖6、牛樟芝經分離所得木質素(lignans)及苯醌衍生物(benzoquinone) 8
圖7、牛樟芝經分離所得琥珀酸 (succinic) 及馬來酸 ( maleic)衍生物 9
圖8、牛樟芝經分離所得抗病毒、抗發炎化合物 9
圖9、BCLC肝癌分期法 16
圖10、細胞壞死與凋亡之型態差異 19
圖11、細胞凋亡之外源性與內源性路徑 20
圖12、牛樟芝子實體萃取物HPLC分析圖譜 47
圖13、將牛樟芝子實體萃取物分區之圖譜 47
圖14、FK5之HPLC分析圖譜 48
圖15、FK5經半製備HPCL純化之Antcin A HPLC分析圖譜 48
圖16、乙醇對HepG2細胞株存活率的影響 49
圖17、牛樟芝子實體乙醇萃取物對HepG2細胞株存活率的影響 49
圖18、純化物Antcin A對HepG2細胞株存活率的影響 50
圖19、市售藥Doxorubicin對HepG2細胞株存活率的影響 50
圖20、市售藥Mitoxantrone對HepG2細胞株存活率的影響 51
圖21、市售藥Docetoxel對HepG2細胞株存活率的影響 51
圖22、市售藥5-FU對HepG2細胞株存活率的影響 52
圖23、市售藥Doxorubicin對NOD-SCID小鼠體重影響 53
圖24、市售藥Mitoxantrone對NOD-SCID小鼠體重影響 53
圖25、Antcin A對NOD-SCID小鼠體重影響 54
圖26、HepG2異種移植動物模型腫瘤表現 54
圖27、HepG2異種移植動物模型腫瘤體積 55
圖28、HepG2異種移植動物模型腫瘤重量 55
圖29、市售抗癌藥物Sunitinib結合antcin A對NOD-SCID小鼠體重影響 56
圖30、HepG2異種移植動物模型腫瘤表現結果 56
圖31、HepG2異種移植動物模型腫瘤體積 57
圖32、HepG2異種移植動物模型腫瘤重量 57
圖33、H&E組織染色有絲分裂表現量 59
圖34、Ki67表現量變化 60
圖35、TUNEL(+)細胞表現量 61
圖36、c-PARP表現量變化 62
圖37、Procaspase-3與caspase-3表現量變化 63
圖38、Procaspase-9與caspase-9表現量變化 64
圖39、Cytochrome C表現量變化 65
圖40、Bax表現量變化 66
圖41、Bcl-xL表現量變化 67
圖42、Bid與tBid表現量變化 68
圖43、Bad表現量變化 69
圖44、Procaspase-8與caspase-8表現量變化 70
圖45、Fas表現量變化 71
圖46、DR5表現量變化 72
圖47、AKT與AKT-p表現量變化 73
圖48、IGF1與IGF1R表現量變化 74
圖49、Antcin A誘導HepG2腫瘤細胞凋亡路徑圖 84




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