抗黴菌藥抑制人類惡性腫瘤細胞生長之分子機制

Studies on the Molecular Mechanisms of Antifungal Agents-induced Human Malignant Cells Growth Arrest

陳容甄(Rong-Jane Chen)

指導教授 ： 李文森

臺北醫學大學/醫學院/醫學科學研究所/碩士(2000年)

摘要

中文摘要 Ketoconazole與Terbinafine 是臨床上時常被使用的口服抗黴菌藥，且Ketoconazole已經被用於治療人體某些依賴荷爾蒙生長的癌症上。本研究證實Ketoconazole與Terbinafine能使癌細胞的生長週期停滯在G0/G1時期，進而抑制癌細胞的生長。藉由流式細胞儀的分析以及細胞生長曲線的分析，我們觀察到Ketoconazole與Terbinafine誘發癌細胞生長週期停滯的效果，在COLO 205 細胞 (具有wild-type p53) 比HT 29 (p53 His 273 突變) 和Hep 3B細胞 (缺少p53基因) 要好。由此我們推論p53的表現和 Ketoconazole與Terbinafine所引發的癌細胞G0/G1時期停滯的過程有某些相關性。我們藉由Ketoconazole或Terbinafine處理的COLO 205細胞中加入p53 antisense oligonucleotides 的實驗來證實這點推論。同時，Ketoconazole與Terbinafine會引起大腸癌細胞株p53，p21，p27等蛋白質表現量增加，且相對的抑制Cyclin D3及CDK4等蛋白質的表現，且Terbinafine誘發HL 60細胞凋亡的發生。在裸鼠的實驗上也證實Ketoconazole及Terbinafine抑制COLO 205腫瘤生長。本研究提出Ketoconazole與Terbinafine誘發大腸癌細胞生長週期停滯的分子機制，也因為Ketoconazole與Terbinafine具備這些效果，我們認為Ketoconazole與Terbinafine可成為具有潛力的癌症治療藥物。

關鍵字

抗真菌劑 ； 細胞週期 ； 細胞凋亡 ； p53 蛋白 ； p21 蛋白 ； 細胞週期停滯

並列摘要

Abstract In this study, we demonstrated that Ketoconazole (KT) and Terbinafine (TB), two widely used oral-antifungal agents inhibit cell cycle progression in human colorectal and hepatic cancer cell lines in G0/G1 phase. Human cancer cells with various p53 statuses were used to investigate the mechanisms of KT- and TB-induced G0/G1 arrest. The results of flow cytometry and cell growth curve analyses revealed that KT and TB-induced growth arrest was more profound in COLO 205 (with wild-type p53) than in HT 29 (p53 His273 mutant) and Hep 3B (with deleted p53). By the way, TB induced apoptosis in HL 60 cells. KT and TB increased the expression of p53, p21, and p27 in cancer cells, and inhibited the expression of CyclinD3 and CDK4 proteins leaded to the growth arrest in human cancer cells. In contrast, the expression of PCNA, as well as cyclin A, D1, and E levels in human cancer cells were not significant change as compared with untreated cells. CDK4 and CDK2 kinase activity from cells treated with KT and TB was markedly inhibited. In nude mice experiments, treated with KT or TB inhibit the growth of human COLO 205 tumor. Taken together, these results suggest universality of KT and TB in cessation of cell proliferation, also make them very attractive agents for use as potential cancer chemotherapeutic agents.

並列關鍵字

antifungal agents ； cell cycle ； apoptosis ； p53 protein ； p21 protein ； cell cycle arrest

參考文獻

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