肺癌是造成全世界最具威脅的癌症之一。 最主要的原因之一是在化學治療後會產生化療抗藥性。牛樟菇(Antrodia cinnamomea, AC)為一中草藥，又名樟芝或牛樟菇，為台灣特有真菌種。 目前已知AC具可能的抗癌作用，但其對肺癌仍無相關研究證實。 我們的實驗目的是探討AC是否可對化療抗藥性肺腺癌細胞株具有可能的毒殺效益。 我們先以臺灣肺腺癌患者的腫瘤檢体建立本土型肺腺癌細胞株，再以2 μg/ml和5 μg/ml不同濃度的化療藥物：順鉑(cisplatin) 建立出具有順鉑抗藥性的肺腺癌細胞株為細胞模式。 分別利用MTT assay、Wound healing assay、Flow cytometry 及Western blot來檢測AC是否會抑制細胞生長效果、細胞遷移能力、調控細胞週期及細胞凋亡及Bax/Bcl-2的蛋白表現量。結果顯示，AC對於肺腺癌細胞株有明顯的劑量依賴性毒殺作用。對具有順鉑抗藥性的肺腺癌細胞株而言，AC可以再提高其毒殺作用。Wound healing assay結果顯示，當AC濃度在20 mg/ml時，對於具有順鉑抗藥性的肺腺癌細胞株有顯著抑制其細胞遷移能力。AC可部分抑制S+G2M期，同時也會增加細胞凋亡比例。細胞凋亡蛋白分子Bax表現量增加和Bcl-2降低，推測AC可能會啟動內原性途徑的凋亡。 我們認為AC可能可以增強毒殺順鉑抗藥性肺腺癌細胞株能力。

Lung cancer is one of the highest threaten cancers in the world. The most problem of the treatment is believed the chemodrug resistance. Antrodia cinnamomea (A. Cinnamomea; AC), a medicinal mushroom in Taiwan, has been shown anticancer activities. To investigate a novel anticancer effectiveness by pretreating patient-derived non-small cell lung cancer cells (NSCLCs) with cisplatin follwed by the administration of AC, the cisplatin-resistant patient derived NSCLCs were established with a 6-period of cisplatin treatments at 2 μg/ml and 5 μg/ml respectively. The capabilities of AC in cytotoxicity, migration, cell cycle, apoptosis and Bax/Bcl-2 proteins were evaluated respectively. Our results showed significant dose-dependent cytotoxicity in patients-derived NSCLCs. The nontoxic dose of AC enhanced the cytotoxicity of cisplatin-resistant patient-derived NSCLCs. The wound healing assay showed significant inhibitory effect in cisplatin-resistant NSCLCs when AC was treated at 20 mg/ml. Additionally, the enhanced apoptotic effect as characterized by increased Bax and decreased protein levels of Bcl-2 and S+G2M phase was reduced by AC treatment. Our results provide the first evidence that AC induced signigicant higher cytotoxicity and triggered intrinsic apoptosis in cisplatin-resistant NSCLCs.

目錄
中文摘要…………………………………………………………………………1
英文摘要…………………………………………………………………………2
致謝………………………………………………………………………………3
目錄………………………………………………………………………………4
圖目錄……………………………………………………………………………8
第一章 緒論
1-1前言…………………………………………………………………………13
1-2肺癌…………………………………………………………………………13
1-2-1分類…………………………………………………………..………14
1-2-2分期……………………………………………………………..……14
1-2-3治療現況……………………………………………………..………15
1-2-4治療瓶頸……………………………………………………..………15
1-3 Cisplatin與肺癌抗藥性的發生……………………………………..…….15
1-4牛樟菇(AC) ………………………………………………………………..16
1-4-1轉移………………………………………………………..…………17
1-4-2細胞週期……………………………………………..………………18
1-4-3細胞凋亡…………………………………………………..…………21
1-5研究目的與實驗策略……………………………………………………....23
第二章 材料與方法
2-1 細胞培養…………………………………………………………………...24
2-2 牛樟菇(AC) ………………………………………………………………..26
2-3 細胞存活率試驗 (MTT assay) ...………………………………………. 27
2-4細胞移行分析 (wound heading assay) …………………………………28
2-5 流式細胞儀分析 (flow cytometry) ………………………………………28
2-6西方墨點法 (Western blot) ……………………………………………....29
2-7 統計與數據分析…………………………………………………………...32
第三章 結果
以臺灣肺腺癌病患檢體建立人類肺腺癌細胞株(Luca)及順鉑誘導抗藥性之肺腺癌細胞株(Luca/CDDP2 及Luca/CDDP5) …………………….………33
3-1 人類肺腺癌細胞株(Luca)及順鉑誘導抗藥性之兩種人類肺腺癌細胞株(Luca/CDDP2 及Luca/CDDP5)細胞生長……………………….….…34
3-2 Cisplatin抑制二種人類肺腺癌細胞株增生能力………………………...34
3-3牛樟菇(AC)抑制二種人類肺腺癌細胞株增生能力……………………...35
3-4 Cisplatin (順鉑) 對人類肺腺癌細胞株的毒殺效應：兩種順鉑誘導抗藥性細胞株之建立………………………………………………………………36
3-5 牛樟菇(AC)對順鉑誘導抗藥性之兩種人類肺腺癌細胞株的毒殺效 應………………………………………………………………………..…37
3-6 使用牛樟菇(AC)合併順鉑(cisplatin)對順鉑誘導抗藥性之兩種人類肺腺癌細胞株之毒殺效應………………………………………………...…....37
3-7 牛樟菇(AC)抑制人類肺腺癌細胞株(A549及Luca)及順鉑誘導抗藥性之兩種人類肺腺癌細胞株(Luca/CDDP2 及Luca/CDDP5)之移行能力..41
3-8 牛樟菇(AC)抑制人類肺腺癌細胞株(A549及Luca)及順鉑誘導抗藥性之人類肺腺癌細胞株(Luca/CDDP2 及Luca/CDDP5)細胞週期之影響..42
3-9牛樟菇(AC)抑制人類肺腺癌細胞株(A549及Luca)及順鉑誘導抗藥性之兩種人類肺腺癌細胞株(Luca/CDDP2 及Luca/CDDP5) 細胞凋亡及壞死之影響………………………………………………………………......43
3-10 牛樟菇(AC)抑制人類肺腺癌細胞株(A549及Luca)及順鉑誘導抗藥性之兩種人類肺腺癌細胞株(Luca/CDDP2 及Luca/CDDP5) 細胞之Bax/Bcl-2蛋白質表現…………………………………………………….46
第四章 討論
4-1 順鉑(cisplatin)抑制四種人類肺腺癌細胞株增生能力……….....………48
4-2 牛樟菇抑制四種人類肺腺癌細胞株增生能力……….....………............48
4-3使用牛樟菇合併順鉑對順鉑誘導抗藥性之兩種人類肺腺癌細胞株之毒殺效應…………………………………………………………………......…49
4-4 牛樟菇抑制人類肺腺癌細胞株(A549及Luca)及順鉑誘導抗藥性之兩種人類肺腺癌細胞株(Luca/CDDP2 及Luca/CDDP5)之移行能力…..…49
4-5 牛樟菇對人類肺腺癌細胞株(A549及Luca)及順鉑誘導抗藥性之兩種人類肺腺癌細胞株(Luca/CDDP2 及Luca/CDDP5)細胞週期之影響…..50
4-6 牛樟菇對人類肺腺癌細胞株(A549及Luca)及順鉑誘導抗藥性之兩種人類肺腺癌細胞株(Luca/CDDP2 及Luca/CDDP5) 細胞凋亡之影響….50
4-7 牛樟菇對人類肺腺癌細胞株 (A549及Luca)及順鉑誘導抗藥性之兩種人類肺腺癌細胞株 (Luca/CDDP2及Luca/CDDP5) 細胞之蛋白質表現…..……………………………………………………………………....51
4-8 總結…………………………………………………………………..........51
參考文獻…………………………………………………………………......... 53

圖目錄
相片1. 牛樟菇純液 (20ml/瓶)......……………………………………………59
相片2. 2.0μg/ml順鉑抗藥性肺腺癌細胞株(Luca/CDDP2)…………………60
相片3. 5.0μg/ml順鉑抗藥性肺腺癌細胞株(Luca/CDDP2)…………………61
圖1. 三種人類肺腺癌細胞株1×105 cells/ml的生長曲線……………....…..62
圖2. 順鉑(Cisplatin)抑制兩種人類肺腺癌細胞株增生能力及其IC50….…..63
圖3. 牛樟菇(AC)抑制兩種人類肺腺癌細胞株增生能力及其IC50………….64
圖4. 順鉑(Cisplatin)對順鉑誘導抗藥性之兩種人類肺腺癌細胞株的毒殺效應及其IC50………………………………………………………….……65
圖5. 牛樟菇(AC)對順鉑誘導抗藥性之兩種人類肺腺癌細胞株的毒殺效應及其IC50………………………………………………………………….…66
圖6. 使用牛樟菇(AC)合併順鉑(Cisplatin)對順鉑誘導抗藥性之兩種人類肺腺癌細胞株之毒殺效應………………………………………....………67
圖7A. 牛樟菇(AC)抑制人類非小細胞肺腺癌細胞株(A549細胞)之移行能力…………………………………………………………………..…...68
圖7B. 牛樟菇(AC)抑制人類非小細胞肺腺癌細胞株(Luca細胞)之移行能力…………………………………………………………………..…...69
圖7C. 牛樟菇(AC)抑制順鉑誘導抗藥性之人類肺腺癌細胞株(Luca/CDDP2細胞)之移行能力……………………………………………………....70
圖7D. 牛樟菇(AC)抑制順鉑誘導抗藥性之人類肺腺癌細胞株(Luca/CDDP5細胞)之移行能力…………………………………………………....…71
圖8A. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(A549細胞)細胞週期之影響……………………………………………………………………......72
圖8B. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(Luca細胞)細胞週期之影響…………………………………………………………..…………....73
圖8C. 牛樟菇(AC)對順鉑誘導抗藥性之人類肺腺癌細胞株(Luca/CDDP2細胞)細胞週期之影響……………………………………………………74
圖8D. 牛樟菇(AC)對順鉑誘導抗藥性之人類肺腺癌細胞株(Luca/CDDP5細胞)細胞週期之影響……………………………………………………75
圖9A. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(A549細胞)細胞凋亡之影響…………………………………………………………..…………....76
圖 9A-1. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(A549細胞)之細胞凋亡Annexin V值的百分比。…………………………………..................77
圖 9A-2. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(A549細胞) 之細胞壞死PI值的百分比。…………………………………………………….78
圖9B. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(Luca細胞)細胞凋亡之影響…………………………………………………………..…………....79
圖 9B-1. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(Luca細胞)之細胞凋亡Annexin V值的百分比。………………………………………………80
圖 9B-2. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(Luca細胞)之細胞壞死PI值的百分比。……………………………………………………..…81
圖9C. 牛樟菇(AC)對順鉑誘導抗藥性之人類肺腺癌細胞株(Luca/CDDP2細胞)細胞凋亡之影響………………………………………………........82
圖 9C-1. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(Luca/CDDP2細胞)之細胞凋亡Annexin V值的百分比。……………………………………83
圖 9C-2. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(Luca/CDDP2細胞)之細胞壞死PI值的百分比。……………………………………………...84
圖9D. 牛樟菇(AC)對順鉑誘導抗藥性之人類肺腺癌細胞株(Luca/CDDP5細胞)細胞凋亡之影響………………………………………………........85
圖 9D-1. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(Luca/CDDP5細胞)之細胞凋亡Annexin V值的百分比。……………………………………86
圖 9D-2. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(Luca/CDDP5細胞)之細胞壞死PI值的百分比。……………………………………………...8
圖10A. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(A549細胞)細胞之Bax/Bcl-2蛋白質表現量…………………………………………….88
圖10B. 牛樟菇(AC)對人類非小細胞肺腺癌細胞株(Luca細胞)細胞之Bax/Bcl-2蛋白質表現量…………………………………………….89
圖10C. 牛樟菇(AC)對順鉑誘導抗藥性之人類肺腺癌細胞株(Luca/CDDP2細胞)細胞之Bax/Bcl-2蛋白質表現量…….........………………….90
圖10D. 牛樟菇(AC)對順鉑誘導抗藥性之人類肺腺癌細胞株(Luca/CDDP5細胞)細胞之Bax/Bcl-2蛋白質表現量…….........………………….91
附錄1. 長庚生物科技股份有限公司-牛樟菇純液(總生菌數、大腸桿菌群、 砷、鉛、汞)SGS檢驗報告…………………………............………92
附錄2. 長庚生物科技股份有限公司-牛樟菇純液(224項常見西藥成份定性分析)SGS檢驗報告……………………………………............……93
附錄3. 長庚生物科技股份有限公司-牛樟菇純液(鎘、銅)SGS檢驗報告………………………………………………………………...….…94
附錄4. 長庚生物科技股份有限公司-牛樟菇純液(農藥定量分析)SGS檢驗報告……………..................……………………………………………95
附錄5. 長庚生物科技股份有限公司-牛樟菇純液(碘-131、銫-134、銫-137)SGS檢驗報告…….........…………………. …….........……..96
附錄6. 長庚生物科技股份有限公司-牛樟菇純液(二氧化硫)SGS檢驗報告………………………………………………………………...….…97
附錄7. 長庚生物科技股份有限公司-牛樟菇純液(黃麴毒、Aflatoxin B1、Aflatoxin B2、 Aflatoxin G1、Aflatoxin G2)SGS檢驗報告……..98

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