臺灣博碩士論文加值系統

研究目的：台灣十大死因之首為惡性腫瘤，而且惡性腫瘤死亡人數逐年增加。因此研發有效且副作用低的治療藥物十分重要
研究方法：本研究首先評估十二種真菌類衍生化合物，包括11種牛樟芝（Antrodia camphorata）衍生物與黑殭菌素B（Destruxin B, DB）對14種人類腫瘤細胞和兩種非轉化細胞的選擇性細胞毒性。再選擇抗癌效果較好的成份進行活體試驗。並進一步研究有效抗癌成份在活體外及在活體的抗癌機制。
研究結果：其中牛樟芝子實體中分離的麥角甾烷（ergostane）三萜類 methyl Antcinate A（MAA），表現出最強有力的廣泛性抗癌作用，在KB細胞、四種不同的口腔癌細胞株（TSCCa，GNM，OC-2，和OEC-M1型）、PANC-1、BT474、 PC-3、OVCAR-3、HeLa細胞與U2-OS細胞皆具有較高的選擇性指數（CC50/IC50）。MAA以劑量依賴性的方式抑制口腔癌的細胞株OEC-M1和OC-2的生長，卻對正常口腔牙齦成纖維細胞無毒性。以西方點墨法測試PC-3細胞的B細胞淋巴瘤-2蛋白（Bcl-2），Bcl-2相關X蛋白（Bax），聚（ADP-核糖）聚合酶（PARP）的蛋白表達發現MAA透過蛋白酶依賴級聯和Bax蛋白介導的線粒體凋亡途徑導致細胞的死亡，不僅肝癌和口腔癌細胞如此，而且在其他類型亦同，包括前列腺癌，並呈劑量依賴性。黑殭菌素B抗癌作用的研究是較少見的，其抗癌機制尚不清楚。黑殭菌素B分離後以高壓液相色譜儀，電噴霧質譜和1H-核磁共振光譜確認其特徵。以（3 - （4,5 - 二甲基-2 - 基）-2,5二苯基溴化法（MTT法）評估黑殭菌素B在體外對癌細胞的影響，結果顯示黑殭菌素B對於HT-29細胞有較好的抑制作用。
由於黑殭菌素B相對於牛樟芝衍生物在人類HT-29細胞有較好抑制作用，且取得容易，並可大量培養，所以選擇在HT-29結腸癌的小鼠異種移植模型進行黑殭菌素B的抗癌作用的研究。觀察到黑殭菌素B有顯著的細胞活性抑制作用且具有時間和劑量依賴性。每天0.6-15mg/kg DB的皮下注射，可安全和有效地抑制大腸癌細胞的生長。黑殭菌素B的治療組觀察到Bax蛋白，裂聚（ADP-核糖）聚合酶和caspase-3活化的表達，而且黑殭菌素B的治療組腫瘤體積（p <0.05）比模擬控制組顯著減少。
結論： MAA，methyl Antcinate B（MAB），dehydroeburicoic acid 和 15α-acetyl-dehydro-sulfurenic acid 在活體外表現出對癌細胞顯著的選擇性細胞毒殺作用。化學修飾這些三萜類化合物可能可以開發更有效的抗癌藥物。活體外對於人類CRC抗癌效果很好的黑殭菌素B，進行動物實驗的結果顯示黑殭菌素B有可能作為一種對人類CRC的新治療劑。

On this study , eleven derivatives from Antrodia camphorata were isolated to evaluate their selective cytotoxicity toward 14 types of human cancer cell and two non-transformed cell types. Among these triterpenoids, methyl antcinate A （MAA） exhibited the most potent broad spectrum of anticancer effects in KB cells, four different oral cancer cell lines （TSCCa, GNM, OC-2, and OEC-M1）, Panc-1, BT474, PC-3, OVCAR-3, HeLa, and U2-OS cells with high selectivity indices （CC50/IC50）. The protein expression of B-cell lymphoma 2 （Bcl-2）, Bcl-2–associated X protein （Bax）, and poly（ADP-ribose） polymerase （PARP） of PC-3 cells tested by western blotting suggested MAA exerts cell death through caspase-dependent cascade and Bax-mediated mitochondrial apoptotic pathway, not only of liver and oral cancer cells but also on other types, including prostate cancer, in a dosedependent manner. In addition to MAA, methyl antcinate B, dehydroeburicoic acid, and 15α-acetyl-dehydrosulfurenic acid also exhibited significant selective cytotoxic effects for respective cancer cells. Modifications of these triterpenoids may allow development of more potent anticancer drugs.
The study of anticancer effects of destruxin B （DB） is rare and its anticancer mechanism remains unknown. The second part of this study was to test the in vitro and in vivo anticancer effects on human HT-29 colorectal cancer （CRC）. DB was isolated and characterized by high pressure liquid chromatography, electrospray ionization mass spectrometry and 1H-nuclear magnetic resonance spectroscopy. （3-（4,5-Dimethylthiazol-2- yl）-2,5-diphenyltetrazolium bromide assay was used to assess the effects of DB on HT-29 cells in vitro. The anticancer effects of DB were investigated in a murine xenograft model of human colon cancer. A significant inhibition of cell viability was observed with DB treatment in time- and dose-dependent manners. DB administered subcutaneously daily at 0.6-15 mg/kg was safe and effective in inhibiting the growth of CRC cells. Expression of Bax, cleaved poly （ADPribose） polymerase and active caspase-3 were observed with DB treatment and the increase in tumor volumes of treated groups were significantly （p<0.05） less than those of the mock-treated group. DB has potential as a new therapeutic agent against human CRC.

中文摘要...............................................................................................Ⅰ
Abstract....................................................................................................Ⅲ
誌謝與感恩...........................................................................................Ⅴ
總目錄...................................................................................................Ⅵ
圖目錄...................................................................................................Ⅷ
表目錄...................................................................................................Ⅸ
第一章 緒論............................................................................................1
第一節 癌症-台灣十大死因之首....................................................1
第二節 癌症治療...............................................................................6
第三節 細胞凋亡...............................................................................9
第四節 抗癌化合物........................................................................25
第五節 研究目的.............................................................................29
第二章 材料與方法.............................................................................30
第一節 提取及分離抗癌化合物...................................................31
第二節 體外抗癌試驗....................................................................34
第三節 活體抗癌試驗....................................................................38
第四節 統計分析.............................................................................41
第三章 結果..........................................................................................42
第ㄧ節 牛樟芝化合物的抗癌試驗結果......................................42
第二節 黑殭菌素Ｂ的抗癌試驗結果..........................................44
第四章 討論..........................................................................................47
第ㄧ節 牛樟芝化合物的抗癌功效...............................................47
第二節 黑殭菌素Ｂ的抗癌功效...................................................50
第五章 結論..........................................................................................52
參考文獻...............................................................................................54
附錄圖....................................................................................................66
附錄表....................................................................................................86
附錄SCI論文...........................................................................................88

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