Ketoconazole
誘發人類前列腺癌細胞株凋亡之分子機制探討 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。
Studies on the Molecular Mechanisms of Ketoconazole-induced Apopt osis in Human Prostate Cancer Cell Lines
In this study, we demonstrated that Ketoconazole (KT), a widely used oral- antifungal agents, can inhibit androgen-dependent prostate cancer cell (LN CaP) and androgen-independent prostate cancer cell (PC-3) proliferation , KT also induce apoptosis in LNCaP cell. In this study, we used androgen-d ependent and androgen-independent prostate cancer cell line to investigate the mechanisms of Ketoconazole-induced apoptosis. In androgen-depende nt prostate cancer cell, DNA fragmentation analysis revealed that apoptosis was induced in a dose dependent manner by Ketoconazole treatment. The c aspase 3 was activated and its specific substrate, poly （ ADP-ribose ） po lymerase, was degraded at 18-24 h after Ketoconazole treatment. But these results did not find in androgen-independent prostate cancer cell. Dose-dep endent 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 ind uction of apoptosis may relate to the existence of androgen receptor.
