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Please use this identifier to cite or link to this item: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/34676

Title: Clozapine透過活性氧誘導MCF-7產生細胞自噬及細胞凋亡
Clozapine induces autophagy and apoptosis in MCF-7 cells through reactive oxygen species
Authors: Ya-Chun Fan
范雅鈞
Contributors: NTOU:Institute of Bioscience and Biotechnology
國立臺灣海洋大學:生物科技研究所
Keywords: 抗精神病藥物;細胞週期停滯;細胞凋亡;細胞自噬;活性氧
antipsychotics;cell cycle arrest;apoptosis;autophagy;reactive oxygen species
Date: 2013
Issue Date: 2013-10-07T02:45:06Z
Abstract: 己知抗精神病藥物具有抑癌的作用,但透過何種分子機制仍未知。實驗室先前的研究結果顯示clozapine能抑制肺癌細胞株A549、 H1299;大腸癌細胞株SW480、HCT116等腫瘤細胞生長。在本研究論文我們以乳癌細胞株MCF-7探討clozapine抗腫瘤機制,利用colony formation assay和MTT assay證實clozapine對乳癌細胞具有抑制能力,clozapine處理經由減少cyclin D1、CDK4/6和促進cyclin dependent kinase inhibitor(CDK inhibitor)表現,使細胞週期停滯在G0/G1 期,同時可以看到在72小時內活性氧(reactive oxygen species; ROS)、細胞自噬(autophagy)和細胞凋亡(apoptosis) 隨著clozapine處理劑量顯著增加,而共同處理抗氧化劑vitamin E (-Tocopherol) 有效降低活性氧,回復clozapine引起的細胞生長抑制,同時也降低clozapine誘導的細胞自噬和細胞凋亡。利用chloroquine抑制clozapine誘發的autophagy,則導致活性氧增加,促進細胞凋亡。本研究結果為首次證明clozapine透過促進細胞週期停滯在G0/G1期抑制乳癌細胞株MCF-7生長,經由ROS調控細胞自噬和細胞凋亡,而細胞自噬透過降低ROS避免細胞凋亡的發生。本研究成果暗示clozapine和細胞自噬抑制劑共同處理能有效促成乳癌細胞株MCF-7凋亡的發生,抑制其生長。
Even though recent studies demonstrated antipsychotics have antiproliferative activity in cancer cell lines, the mechanisms are not fully elucidated. Clozapine has inhibitory effect on cell growth in MCF-7 cells by MTT and clonogenic assay. Flow cytometric analysis exhibited that the exposure of MCF-7 cells to clozapine led to the G0/G1 phase arrest by decreasing CyclinD1, CDK4, CDK6 and increasing CDK inhibitor p21 and p27 protein levels. Exposure of MCF-7 cells to increasing dosage of clozapine during 72 h significantly increased the production of reactive oxygen species (ROS), apoptosis and autophagy. A ROS scavenger vitamin E reduced ROS, apoptosis and autophagy, then recoveried cell survival. Blocking autophagy by chloroquine could increase clozapine-induced ROS and promoteclozapine-induced apoptosis. Our study proved for the first time that clozapine inhibited MCF-7 cell growth by inducing G0/G1 cell cycle arrest, apoptosis and autophagy via a ROS dependent manner. Clozapine-induced autophagy decreased ROS to protect cancer cell from apoptosis. These data suggested that combined clozapine and autophagy inhibitor will effectively kill MCF-7 cancer cells.
URI: http://ethesys.lib.ntou.edu.tw/cdrfb3/record/#G0010136025
http://ntour.ntou.edu.tw/handle/987654321/34676
Appears in Collections:[生命科學暨生物科技學系] 博碩士論文

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