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研究生:張永佳
研究生(外文):Yung-Chia Chang
論文名稱:抗精神病藥物clozapine抑制肝癌細胞生長之分子機制
論文名稱(外文):Molecular Mechanisms of Antipsychotic Clozapine-Induced Cell Growth Inhibition in Hepatocellular Carcinoma
指導教授:陳秀儀陳秀儀引用關係
指導教授(外文):Shiow-Yi Chen
學位類別:碩士
校院名稱:國立臺灣海洋大學
系所名稱:生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:91
中文關鍵詞:抗精神藥物肝癌細胞clozapine
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Clozapine為臨床上最後一線抗精神病用藥,對頑固型精神分裂症患者有很好的療效。臨床上統計服用抗精神病藥物之精神分裂症患者,其罹患癌症機率相較於一般人來的低(Barak et al., 2005; Grinshpoon et al., 2005),但原因並不清楚,故本論文擬探討是否抗精神病藥物可以降低癌症的產生。在本論文選用肝癌細胞株HepG2偵測clozapine抑癌之能力。初步結果顯示clozapine可以time-及dosage-dependent方式抑制HepG2的生長,同時以clonogenic assay確認此結果。此外,目前的實驗結果亦證實clozapine可以time-及dosage-dependent方式增加HepG2活性氧 (reactive oxygen species; ROS)及細胞自噬作用 (autophagy);另外,clozapine也造成HepG2產生老化現象。綜合上述的結果,是否活性氧、細胞自噬作用及老化牽涉clozapine抑制肝癌細胞株HepG2生長之分子機制,則有待未來進一步研究的釐清。
Clozapine, the last line drug for schizophrenia, has good effect on treating refractory schizophrenia patients. Clinical studies indicated that schizophrenia patients taking antipsychotics have less incidence of developing cancer than other normal people, but such a phenomenon remains to be explored. Therefore, this study is to investigate whether antipsychotics can decrease vulnerability to cancer. Here, HepG2, a hepatoma cell line, is used to evaluate the antitumor ability of clozapine. Preliminary results showed that clozapine inhibited HepG2 cancer cell growth in both time- and dosage-dependent manners by cell proliferation and clonogenic assay. Clozapine also induced cell cycle arrest in Go/G1 phase. Besides, we also demonstrated clozapine could increase ROS (reactive oxygen species), autophagy and senescence in HepG2 cancer cells. Autophagic marker LC3, but not Beclin-1 also confirmed that clozapine can promote autophagy. Whether ROS, autophagy and senescence are involved in inhibition of clozapine on HepG2 needs to be further examined.
目錄
縮寫……………………………………………………………………………………i
謝辭……………………………………………………………………………………...v
中文摘要………………………………………………………………….....................vi
英文摘要……………………………………………………………..………………vii
目錄………………………………………………………………………………….viii
圖目錄………………………………………………………………………….............xi
第一章  緒論…………………………………………………………………………..1
第二章  文獻回顧…………………………………………………………………...2
第一節 抗精神病藥物(Antipsychotics).................................................................2
1.1 精神分裂症之流行病學………………………………………….…….2
1.2 精神分裂症之特徵……………………………….…………….………2
1.3 精神分裂症之治療…………………………………..…………………3
1.4 Clozapine………………………………………………………….…….5
第二節 肝癌 (Hepatocellular carcinoma, HCC)………………………………...8
    2.1 肝臟與肝癌……………………………………………………………..8
    2.2 肝癌之流行病學、病理學及病原學…………………………………..10
      2.2.1 流行病學………………………………….…………………....10
      2.2.2 病理學………………………………………………………..11
      2.2.3 病原學…………………………………………………..……12
    2.3 肝癌之分類……………………………………………………………15
    2.4 肝癌之診斷與治療……………………………………………………17
2.4.1 臨床診斷……………………………………………………….17
2.4.2 肝癌治療……………………………………………………….19
第三節 訊息傳遞路徑 (Signal transduction pathway)………………...………24
3.1 有絲分裂原活化蛋白激酶之調控…...……………………………….24
3.2 磷酸肌醇3激酶/蛋白激酶B之調控………………………………....25
3.3 Wnt/β-catenin signaling pathway之調控……………………………..26
3.4 生長因子以及血管新生因子…………………………………………27
第四節 細胞週期 (Cell cycle)……………………………………..…………..28
4.1 細胞週期的生理作用…………………………………………………28
4.2 細胞週期的調控……………………………………………...……….30
4.3 細胞週期與癌症之相關性……………………………………………32
第五節 活性氧 (Reactive oxygen species, ROS)………………………...……33
5.1 ROS的產生與生理意義…………………………………………...….33
5.1.1 ROS之種類……………………………………………………33
5.1.2 ROS之來源……………………………………………………33
5.1.3 ROS之生理功能………………………………………………35
5.1.4 ROS之損傷………………………………………..…………..35
5.2 ROS與癌症……………………………………………………...……36
第六節 細胞自噬 (Autophagy)………………………………………….…….38
第七節 細胞老化 (Senescence)……………………………………………….41
第三章 研究目的…………………………………………………………………….45
第四章 實驗材料與方法…………………………………………………………….46
第一節 實驗藥品與材料……………………………………………………….46
第二節 實驗藥品配置及儲存………………………………………………….47
第三節 實驗方法……………………………………………………………….49
3.1 細胞培養 (Cell culture)……………………………………………….49
3.1.1 細胞培養與繼代 (Subculture)………………………………….49
3.1.2 細胞冷凍…………………………………………………...……50
3.1.3 細胞解凍………………………………………………………...50
3.1.4 細胞增生分析 (Trypan blue staining)………………………….50
3.1.5 克隆檢驗 (Clonogenic assay)…………………………………..51
3.2 流式細胞儀分析 (Flow cytometric analysis)…………………...……51
3.2.1 細胞固定作用 (Fixation)……………………………………….51
3.2.2 細胞週期分析 (Cell cycle analysis)…………………………….52
3.2.3 活性氧測定 (ROS analysis)…………………………………….52
3.3 細胞轉染 (Transfection)……………………………………...………53
3.4 蛋白質電泳分析………………………………………………………54
3.4.1 蛋白質萃取與定量…………………………………………….54
3.4.1.1 蛋白質萃取………………………………………………54
3.4.1.2 蛋白質濃度定量…………………………………………54
3.4.2 電泳 (SDS-Polyacrylamide gel electrophoresis)………………55
3.4.3 西方墨點法 (Western blot analysis)…………………………..55
3.5 細胞老化測試 (Seniscence-associated β-galactosidase activity assay, SA-β-gal assay)………………………………………………………...57
3.5.1 細胞固定作用 (Fixation)…………………...…………………57
3.5.2 細胞染色 (SA-β-gal staining)…………………………………57
第五章 結果………………………………………………………………………….58
一、 clozapine抑制HepG2之生長…………………………………………...58
二、 clozapine促使細胞週期停滯於G0/G1時期..........................................58
三、 clozapine藉由p21與p27促使細胞週期停滯………………………….59
四、 clozapine可誘導HepG2內ROS產量增加……………………………..60
五、 clozapine可引發細胞自噬作用………………………………………….61
六、 clozapine可導致細胞老化現象………………………………………….62
第六章 討論………………………………………………………………………….63
第七章 參考文獻…………………………………………………………………….66

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