Ketoconazole誘發人類前列腺癌細胞株凋亡之分子機制探討

Studies on the Molecular Mechanisms of Ketoconazole-induced Apoptosis in Human Prostate Cancer Cell Lines

洪苓方(LingFang Hung)

指導教授 ： 何元順

臺北醫學大學/醫學院/醫學檢驗生物技術學研究所/碩士(2001年)

摘要

Ketoconazole這個廣效性的抗黴菌藥物，是臨床上時常被使用的口服抗黴菌藥，其可抑制睪丸及腎上腺的類脂醇生成，因此Ketoconazole被用於治療人體某些依賴荷爾蒙生長的癌症上。藉由細胞生長曲線的分析，我們觀察到Ketoconazole可抑制前列腺癌細胞生長停滯，本研究證實Ketoconazole能抑制前列腺癌細胞的生長。此外在LNCaP睪固酮依賴性前列腺癌細胞(androgen-dependent prostate cancer cell)，由DNA膠體電泳可觀察到DNA呈現由大至小分子量的階梯狀，顯示Ketoconazole會造成LNCaP細胞的凋亡。此外，從蛋白的表現我們發現Ketoconazole會引起前列腺癌細胞株p53蛋白表現量增加，且活化Bax等蛋白的表現，而且Ketoconazole會經由活化caspases誘發細胞凋亡的發生。雖然細胞凋亡的發生並未在PC-3睪固酮依賴性前列腺癌細胞(androgen-independent prostate cancer cell)中觀察到，但是仍可看見p53與Bax蛋白的表現量因Ketoconazole的刺激而增加。由以上結果，我們推測Ketoconazole抑制人類睪固酮依賴性前列腺癌細胞的生長可能是因誘發了前列腺癌細胞凋亡的分子機制所造成，而引發此機制的訊息傳遞可能與睪固酮受體(androgen receptor)的存在與否有關。

關鍵字

細胞凋亡 ； 前列腺癌

並列摘要

In this study, we demonstrated that Ketoconazole (KT), a widely used oral-antifungal agents, can inhibit androgen-dependent prostate cancer cell (LNCaP) and androgen-independent prostate cancer cell (PC-3) proliferation ,KT also induce apoptosis in LNCaP cell. In this study, we used androgen-dependent and androgen-independent prostate cancer cell line to investigate the mechanisms of Ketoconazole-induced apoptosis. In androgen-dependent prostate cancer cell, DNA fragmentation analysis revealed that apoptosis was induced in a dose dependent manner by Ketoconazole treatment. The caspase 3 was activated and its specific substrate, poly（ADP-ribose）polymerase, was degraded at 18-24 h after Ketoconazole treatment. But these results did not find in androgen-independent prostate cancer cell. Dose-dependent experiment was performed and demonstrated that the p53 and Bax gene expression was elevated both in these two cells. Taken together, these results suggest that KT in cessation of androgen-dependent prostate cancer cell proliferation, that may cause by the induction of apoptosis and this induction of apoptosis may relate to the existence of androgen receptor.

並列關鍵字

Apoptosis ； Prostate cancer

參考文獻

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