真菌二級代謝物 Cephalochromin 抑制鼻咽癌細胞相關機制之探討; Study on the Mechanisms of Anticancer Activity of a Fungal Secondary Metabolite, Cephalochromin, in Nasopharyngeal Carcinoma Cells

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題名:	真菌二級代謝物 Cephalochromin 抑制鼻咽癌細胞相關機制之探討;Study on the Mechanisms of Anticancer Activity of a Fungal Secondary Metabolite, Cephalochromin, in Nasopharyngeal Carcinoma Cells
作者:	林振邦;Cheng-Pan Lin
貢獻者:	中國醫藥大學：藥學系碩士班
關鍵詞:	惡性腫瘤;抗腫瘤藥物;真菌;鼻咽癌;細胞週期停滯;細胞凋亡;caspase-8;malignant tumor;cancer;antitumor agent;fungus;nasopharyngeal carcinoma;cell cycle arrest;apoptosis
日期:	2009-07-01
上傳時間:	2009-08-13 10:54:06 (UTC+8)
摘要:	根據行政院衛生署 97 年國人主要死因統計，惡性腫瘤連續 27 年蟬聯首位。面對腫瘤病例逐年增加的趨勢，但在治療面上抗腫瘤藥物逐漸產生抗藥性而導致療效不佳，所以新的抗腫瘤藥物的研發顯得刻不容緩。目前抗腫瘤藥物的研發除從植物，動物中純化分離，甚至可以由真菌為來源得到有效具抗腫瘤活性的化合物。我們先前由真菌 Cosmospora vivior ( 株系名稱 89051501 ) 中分離出數個純化物，其中，cephalochromin 對多種癌細胞都有良好的抑制效果。為了進一步探討其抗腫瘤之機轉，我們選擇了對 cephalochromin 較敏感的 HONE-1 及 NPC-TW01 人類鼻咽癌細胞株進行抗癌機轉的研究。流式細胞分析的結果發現 cephalochromin 會造成細胞週期停滯在細胞週期中 G1 期，此停滯的現象不但和化合物濃度有依從關係，甚至和化合物處理細胞株的時間有依從關係。同時，我們也發現當化合物處理細胞 72 小時，會有 sub-G1 期的產生。我們利用 Hoechst 33258 / propidium iodide 的雙染實驗和 Annexin V-FITC apoptosis detection kit 的偵測，發現 cephalochromin 產生/造成細胞死亡的特徵是經由細胞凋亡路徑所引發。由於 Fas 是一個 p53 的調節蛋白，進一步的研究結果也顯示 p53 及其下游蛋白，也受到 cephalochromin 的作用而活化。因此，我們推斷，cephalochromin 可以藉由活化 Fas / FasL，進而啟始 p53 及 caspase-8 依附的訊息路徑而造成鼻咽癌細胞凋亡。綜此，cephalochromin 為一極具潛力的新穎抗癌物質，值得進一步發展。 According to the recently information release from the Department of Health, the malignant tumor is the number 1 cause of death in Taiwan for the last 27 years. Although, several great improvement have been established for treating cancer, developing the drug resistance by the cancer cells causes the curative effect generally not good. Therefore, the new antitumor medicine''s research and development appear urgent. At present the source of antitumor agents is major isolated or derivatives from the plant or the animal, but recently, several studies demonstrated that the fungus also obtain the effective anti-tumor active compounds. In this study, we identified a fungal secondary metabolite, cephalochromin, which posseses a strong antitumoral activity against several human cancer cell lines. Since cephalochromin exerts comparably great anti-proliferative effect toward human nasopharyngeal carcinoma HONE-1 and NPC-TW01 cells, we therefore investigated the mechanisms of action of anticancer efficacy of cephalochromin in this type of cancer. Results demonstrated that cephalochromin induces cells arrest in the G1 phase in the time- and doseage-dependent manner. Significant appearance of sub-G1 population and Annexin V-positive cells indicates that cephalochromin-induced cell death proceeded through an apoptotic pathway. Furthermore, we found that cephalochromin only activate the caspase-8, but not caspase-9. The finding that cephalochromin-induced apoptosis through a memebrane-mediated mechanism was supported by up-regulated expression of Fas and FasL. Furthermore, up-regulation of p53 was found after cephalochromin exposure. Above results indicated that cephalochromin is a effective anticancer agent which could induced cancer cell apoptosis through a p53-mediated caspase-8 / Fas-FasL-dependent pathway and worth for further development.
顯示於類別:	[藥學系暨碩博士班] 博碩士論文

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