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研究生(外文):YU-HAO LUO
論文名稱(外文):The apoptotic mechanism of specific compound purified from Antrodia cinnamomea’s fruiting body in prostate carcinoma xenograft model
指導教授(外文):Tzong-Zeng Wu
外文關鍵詞:prostate cancerAntrodia cinnamomeaanti-cancerin vivoxenograftIntrinsic apoptosis pathwayextrinsic apoptosis pathwayp53
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前列腺癌是男性中年後容易罹患的癌症之一,由於飲食習慣的西化,導致前列腺癌的發生率及死亡率逐年增高。牛樟芝為一種獨特的真菌植物,僅生長於陰暗、腐朽的牛樟樹,而牛樟樹為產量稀少、珍貴為台灣特有保育植物。牛樟芝含有豐富的三萜類、多醣體等,具有多種藥理活性如:抗腫瘤、保肝、抗氧化等。本實驗目的是在體外 ( in vitro ) 及活體實驗 ( in vivo ) 中探討牛樟芝子實體分離物,對於抑制前列腺癌細胞生長的分子作用機制。實驗主要分為三部分,首先,篩選出能有效抑制前列腺癌細胞生長的特定牛樟芝子實體純化物。利用MTT assay篩選牛樟芝子實體粗萃物 FK1 ~ FK6 ,其中以 FK5 抑制效果最好,對於前列腺癌細胞株 PC-3, LNCaP 半抑制率分別約為70.36 μg/ml 及52.95 μg/ml ,再將 FK5以 HPLC 半製備分離純化出 K5-2 ,其抑制 PC-3, LNCaP 半抑制率皆約為2.5 μg/ml ;接著測試 K5-2 對正常細胞株 CCD-966SK 之毒性,結果顯示 K5-2 濃度10 μg/ml以下不會抑制其生長;以顯微鏡觀察發現 K5-2 處理後,細胞出現皺縮以及許多碎片產生,再藉由流式細胞儀分析, K5-2 使 LNCaP 細胞週期停滯在SubG1,但PC-3沒有顯著改變,而 PC-3 及LNCaP 皆因 K5-2 處理而有凋亡產生。第二部分利用動物模型觀察牛樟芝子實體分離物在活體內對於腫瘤影響。異種移植前列腺癌細胞 PC-3 誘導免疫缺陷小鼠 ( NOD-SCID ) 長出前列腺腫瘤,以腹腔注射 ( i.p. ) K5-2 ,在濃度10 mg/kg 下,能有效抑制腫瘤體積及重量,接著在組織上以 TUNEL Assay 觀察到隨K5-2 濃度提高,細胞凋亡比例跟著增加。最後利用腫瘤萃取得到之蛋白進行細胞凋亡途徑之分析。 K5-2 會使前列腺癌細胞經由內源性及外源性凋亡途徑, DR4/DR5 及Fas 這些死亡受器表現量增加, Caspase-8 被活化,抑制Bcl-2表現並活化Bax 及Bad ,使粒線體內 Cythchrome C 釋出活化下游 Caspase-9 ,而後 Caspase-3 被活化走向凋亡,同時抑制 PARP 修復 DNA 之能力,增加 p53 表現,間接導致細胞凋亡。 由以上結果可知, K5-2 有很好的潛力當作治療前列腺癌之菇菌來源藥物,且不會對正常細胞造成傷害。
Prostate cancer is one of the susceptible diseases observed among older men. Due to the gradual westernization of dietary and lifestyle habits, leading to prostate cancer incidence and mortality rates increased year by year. Antrodia cinnamomea (AC) is an unique mushroom that grows in dark and humid conditions, and it specifically prefers to grow on the inner caving of the endemic species Cinnamomum kanehirae ( Bull camphor tree ), which is a very rare and one of conservation plants in Taiwan. AC contains abundant triterpenoids and polysaccharides, lot of previous researches have shown that AC has many pharmacological effects such as anti-cancer, hepatoprotective, and anti-oxidant, etc. The purpose of this study was to investigate the cytotoxic effect and molecular mechanism of AC’s bioactive components in prostate cancer cell lines both in vitro and in vivo with xenograft mode. This study was mainly divided into three parts: first, the main aim is to screen out the target compound from AC's fruiting body which can effectively inhibit the growth of prostate cancer cells. The results of MTT assay showed that FK5 expressed best inhibitory effect (IC50 70.36 μg / ml and 52.95 μg / ml in PC-3 and LNCaP, respectively) among all test fractions (FK1 to FK6). After that, K5-2 was further purified from FK5 by using semi-preparative HPLC column, which inhibits both PC-3 and LNCaP with IC50 were approximately 2.5 μg / ml but no toxicity to the normal cell CCD-966SK up to the concentration of 10 μg / ml. Microscopic examination found that many changes in cell morphology such as shrinkage and fragmentation after K5-2 treatment. Flow cytometry analysis showed that LNCaP’s after K5-2 treatment resulted in cell cycle arrested at SubG1 phase, but no significant change in PC-3. However, Annexin-V FITC & PI double staining showed that the percentage of apoptotic cells of PC-3 and LNCaP were increased with the concentration of K5-2 and reached a maximum at 5 μg / ml. The second part of this study was to investigate the effect of K5-2 on PC-3 cells in vivo by using xenograft in NOD-SCID mice to induce prostate tumors grow. Intraperitoneal injected series dosages of K5-2 in NOD-SCID mice; the results showed that K5-2 could effectively suppress the tumor volume and mass at concentration level of 10 mg/kg. Subsequently, TUNEL Assay showed that the proportion of apoptotic cells increased with K5-2 in dose-dependent manner. Finally, to elucidate the apoptotic pathway by using protein extracts from homogenized tumor tissue, Western blot results showed that K5-2 induced apoptosis both associated with intrinsic and extrinsic pathway. The results were summary as followings: both DR4 / DR5 and Fas death receptors were triggered and Caspase-8, -3 were activated after K5-2 treated. Down-regulation of Bcl-2 and up-regulation of Bax, Bad were observed along with the release of Cytochrome C. Subsequently, the level of Caspase-9, -3 were activated which induced apoptosis. The activation of Caspase-3 suppressed the PARP level which could repair DNA. Furthermore, the up-regulation of p53 was observed, which indirectly impacted apoptosis. Therefore, our results suggest that K5-2 may have a great potential to develop as a drug originating from medicinal fungus AC for prostate cancer treatment and will not damage normal.
中文摘要 I
Abstract III
目錄 V
圖目錄 IXX
表目錄 XV
附錄目錄 XVIII
第壹章、前言 1
第貳章、文獻回顧 3
一、 前列腺癌 3
A. 前列腺構造與特性 3
B. 前列腺癌 4
C. 前列腺癌之診斷 5
D. 前列腺癌之分期 6
E. 前列腺癌治療 7
二、 牛樟芝 9
A. 分類與命名 9
B. 生長環境與型態 10
C. 一般成分在菌絲體與子實體之差異 11
D. 活性成分 13
E. 藥理作用 18
三、 細胞凋亡 22
A. 細胞凋亡 22
B. 細胞凋亡路徑 23
第參章、研究目的 25
第肆章、實驗架構 27
第伍章、實驗材料與方法 29
一、 牛樟芝子實體樣本製備 29
A. 牛樟芝子實體萃取 29
B. 管柱層析法 29
C. HPLC半製備分離、純化與樣本保存 30
D. HPLC分析 31
二、 細胞實驗 ( in vitro ) 31
A. 前列腺癌細胞培養與繼代 31
B. 前列腺癌細胞存活率測試 34
C. 前列腺癌細胞週期分析 35
D. 前列腺癌細胞凋亡測試 36
三、 動物實驗 ( in vivo ) 38
A. 實驗動物 38
B. 實驗方法 38
C. 病理組織切片 40
D. 西方墨點法 ( Western ) 41
E. 統計分析 43
第陸章、實驗結果 45
一、 牛樟芝子實體樣本製備 45
A. 牛樟芝子實體萃取 45
B. 管柱層析 45
C. FK5 半製備 HPLC 純化分離 45
D. 半製備 HPLC 純化分離 K5-2 45
二、 細胞實驗 ( in vitro ) 46
A. 細胞存活率測試 46
B. 細胞形態變化 49
C. 細胞週期測試 50
D. 細胞凋亡測試 51
三、 動物實驗 ( in vivo ) 53
A. K5-2 處理對於小鼠體重之影響 53
B. K5-2 處理後腫瘤體積與重量 54
C. 腫瘤組織切片 54
D. K5-2 處理之腫瘤萃取蛋白探討細胞凋亡之訊息傳遞 55
第柒章、討論 103
第捌章、結論 115
第玖章、未來展望 117
第拾章、參考文獻 119

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