中藥南柴胡純化物新穎 r 丁內酯化合物 isochaihulactone經由調控microRNA 對抗攝護腺腫瘤機轉與雄性素受體的調控

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题名:	中藥南柴胡純化物新穎 r 丁內酯化合物 isochaihulactone經由調控microRNA 對抗攝護腺腫瘤機轉與雄性素受體的調控
作者:	韓鴻志(Horng-Jyh Harn);邱紫文;林振東
贡献者:	醫學院醫學系學士班病理學科;中國附醫病理部
关键词:	異柴胡內酯；微小RNA；雄性素接受體；攝護腺癌
日期:	2011-07-31
上传时间:	2012-06-15 11:37:03 (UTC+8)
摘要:	攝護腺癌目前的治?著重在抑制雄性素在體內濃?，然而往往會?發成非雄性素依賴性，所以發展新藥對抗攝護腺腫瘤是迫?需的。在我們實驗中從中藥南柴胡篩選到的全新純化物新穎 r 丁內酯化合物(4-benzo[1,3]dioxol-5- ylmethyl-3 (3,4,5-trimethoxyl- benzylidene) -dihydro-furan-2-one) 分子?為 398.41 kDa，簡稱 K8。我們初步研究發現 K8 對表現雄性素受體 androgen receptor (AR) 的攝護腺癌細胞株 LNCaP 有顯著生長抑制效果 (IC50=1±0.2 μM)，且相較於?表現 AR 的 PC-3 (IC50=100±0.8 μM) 與 DU145 (IC50=120±0.6μM) IC50 相差大於 100 倍。我們由 RT-PCR 發現 AR 與攝護腺特?抗原 (PSA) 的表現?會隨著 K8 作用時間增加而抑制。在初步?鼠?位移植腫瘤 (nude mice xenograft tumor model) 之治? 模式進?體內實驗，發現以15 mg/kg 較低劑? K8 可以抑制 60 % 的?鼠腫瘤細胞生長。腫瘤組織的免疫染色也證實 AR 表現隨著 K8 劑?上升而抑制?多。進一步比較 K8 調控的 miRNA，在 LNCaP 發現 mir-21 與 mir-106b 的表現隨著作用時間增加而抑制?多。初步實驗證實 K8 可抑制 AR 的表現，所以我們第一?要確認 K8 的毒?與 AR 的表現有關。第二?探討 K8 調控 AR 與 miRNA 的關係，並歸??床組織中 miRNA 表現型。第三?以最適當評估平台應用於?鼠皮下攜帶?螢光人?攝護腺腫瘤動物模式，以?同劑? K8 評估腫瘤大小、細胞毒?作用及動物存活? 分析。因此本計畫將以三株人?攝護腺癌的細胞株 LNCaP、PC-3 和 DU145 ，將進 ? real-time PCR、CHIP、miRNA microarray、tissue array 等方式及?螢光腫瘤動物模式?探討 K8 治?攝護腺癌的?效評估，希望能提供日後?床治?的一潛? 藥物 On the average, the prostate cancer therapy is emphasize that suppress androgen, Because prostate cancer cells rely on androgens for proliferation and survival. However, the effectiveness of androgen deprivation therapy is temporary, and tumors in the majority of patients eventually relapse and evolve into castration resistant prostate cancer (CRPC). We previously demonstrated that the crude acetone extract of Bupleurum scorzonerifolium (BS-AE) and its active anti-proliferative component ,(4-benzo[1,3]dioxol-5- ylmethyl-3 (3,4,5-trimethoxyl-benzylidene) -dihydro-furan-2-one).The molecular weight is 398.41 kDa, abbreviated as K8.On preliminary report, we demonstrate k8 have anti-proliferation activity and apoptosis effects on prostate cancer cells K8 was cytotoxic (IC50=1±0.2 μM) in this androgen receptor (AR) positive prostate cancer cell, compare with AR negative cells PC-3 (IC50=100±0.8 μM) and DU145 (IC50=120±0.6μM) differ 100 times. In our preliminary data, injection 15mg/kg curative effect in nude mice xenograft tumor model can inhibit tumour about 60 percentage . The immunohistochemistry (IHC) and RT-PCR confirm that AR expression was inhibits more as K8 dosage rises and time dependent. Further compare miRNA that K8 controls, find mir-21 and mir-106b apparent inhibited in LNCaP cells. We find K8 can inhibit AR expression and with dosage and time dependent, so we will confirm the effcet was relating to AR by K8 in the first year. To investigate K8 affect relation between AR and miRNA in the second year. The third year, by most appropriate to assess platform apply nude mice with LNCaP cell carry green fluorescent protein under the skin, assess tumour size, cell and cytotoxic effect and survival rate analysis with different K8 dosage. In this report, we use LNCaP、PC-3 and DU145 to apply to real-time PCR CHIP, miRNA microarray, tissue array and LNCaP-GFP nude mice model, hope to offer a potentiality medicine of clinical treatment in the future
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