https://scholars.lib.ntu.edu.tw/handle/123456789/188164
標題: | 皮質類固醇及非類固醇抗發炎劑對癌細胞藥物敏感性的影響及相關機轉之研究(3/3) | 其他標題: | Study on the effects and mechanisms of action of glucocorticoids and non-steroidal anti-inflammatory drugs on the drug sensitivity of common solid tumors | 作者: | 鄭安理 | 關鍵字: | 皮質類固醇;癌細胞;化學藥物感受性;Glucocorticoids;Carcinoma cell;Chemosensitivity | 公開日期: | 2002 | 出版社: | 臺北市:國立臺灣大學醫學院內科 | 摘要: | 皮質類固醇除本身對於某些血液腫瘤 具細胞毒性之外,也常與抗癌化學藥物併 用以治療因化學藥物引起之噁心、嘔吐及 過敏反應等副作用。雖然類固醇己被証實 可以影響多種細胞之重要訊息傳遞徑路, 其中有些與癌細胞抗藥性有關。然而我們 對類固醇類藥物對於與一般癌細胞生長以 及化學藥物感受性可能產生之影響仍所知 極少。釐清這個問題對臨床腫瘤治療將會有重要影響。在此研究中,我們隨機選擇了十四株 癌細胞株有系統地進行研究以解答這個問 題。Dexamethason (DEX )被選為皮質類固醇代表藥物。我們發現:1. DEX 確實對癌細胞株(十四株之中的七株)的生長以及化學藥物感受性有影響。DEX 對癌細胞的影響呈現異質性而 且似乎是彼此互斥的。DEX 抑制四株細胞的生長(MCF-7 ,MCF/MXR1 ,MCF/TPT300 及HeLa 細胞),提高了一 株細胞對cisplatin 的化學藥物感受性 (SiHa),並降低兩株細胞對cisplatin 的化學藥物感受性(H460 及Hep3B)。2. 此影響是皮質類固醇受體—依賴性的。因為DEX 有影響的七株細胞的皮質類固醇受體濃度比其他七株不受DEX 影響的細胞高許多(5.2 ±2.5 ×10 4 vs 1.3 ±1.4 ×10 4 , P=0.005)。3. 造成這些DEX 異質性影響的相關機轉也相同地是異質性而且彼此互斥。DEX 在SiHa 細胞所造成的化學藥物致敏感 效應與其對NF-kB 的調控有著高度相 關。對於MCF-7 ,MCF/MXR1 及 MCF/TPT300 細胞造成的生長抑制效應 與G1 細胞週期停止及p21 蛋白上升調 控有關。而DEX 在H460 細胞造成的 化學藥物抗藥性則與Bcl-2 蛋白上升調 控有關。 4. 在SiHa ,H460 及Hep3B 等三株會因 為DEX 處理而改變化學藥物敏感性的 細胞株中,多重性抗藥基因MDR1 及 MRP 的表現量及活性並不受DEX 的影 響。 5. 在此十四株細胞中非類固醇抗發炎劑 對化學藥物敏感性沒有影響。 Background: Although high-dose of glucocorticoids (GCs) are commonly co-administered with anti-cancer drugs to prevent drug-induced allergic reaction, nausea, and vomiting, little is known regarding the effects of GC on the growth or chemosensitivity of common human carcinomas. Methods: Ten carcinoma cell lines were randomly selected to assess the effects of GC on chemosensitivity. Cellular GC receptor (GCR) content was determined by using 3 H-labelled dexamethasone (DEX). Growth inhibition was estimated by MTT assay. Cell cycle phases and apoptosis were analyzed by flow cytometry. DNA-binding activity of NF-B was measured by electrophoretic mobility shift assay (EMSA). The expression of p53, p21, p27, cyclin D1 and Bcl-2 family was determined by Western blot. Results : DEX had effects on either growth or chemosensitivity in 7 of the 14 cell lines. DEX inhibited cell growth of 4 (MCF-7, MCF-7/MXR1, MCF-7/TPT300, and HeLa), increased cisplatin cytotoxicity of one (SiHa), and decreased cisplatin cytotoxicity of 2 (H460 and Hep3B) cells lines. The GCR contents of the 7 cell lines affected by DEX were significantly higher than those of the other 7 cell lines unaffected by DEX (5.2 ±2.5 ×10 4 vs 1.3 ±1.4 ×10 4 , P=0.005) suggesting GCR is the pivotal mediator of the effect of DEX on carcinoma cell. Further, transfection of a vector encoding GCR to a GCR low-expressing cell line (AGS) increased its susceptibility to the effect of DEX. The possible mediators of the heterogeneous effects of DEX on these carcinoma cells were screened. The growth inhibitory effect of DEX was found associated with cell cycle phase regulation. DEX induced p21 up-regulation and G1 arrest in MCF-7, MCF-7/MXR1, and MCF-7/TPT300; and caused G2/M arrest in HeLa cells. The cell cycle phases of all other cell lines were not affected by DEX. The cytotoxicity-enhancing effect of DEX on SiHa cells correlated well with its effect on NF-B activity: DEX suppressed cisplatin-induced NF-B activation exclusively in SiHa cells, and expression of a dominant-negative truncated I B gene completely abolish this effect of DEX. The NF-B activity of all other cell lines was either not affected by cisplatin or the cisplatin-activated NF-B not suppressible by DEX. Finally, DEX up-regulated Bcl-2 exclusively in H460, one of the two cell lines in which DEX induced cisplatin resistance. Conclusions :GCs affect growth or cisplatin chemosensitivity in some carcinoma cells. Whether this in-vitro observation is of clinical relevance and the molecular mechanisms mediating the heterogeneous GCR-dependent effect of GC on carcinoma cells need to be clarified. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/23556 | 其他識別: | 902314B002247 | Rights: | 國立臺灣大學醫學院內科 |
顯示於: | 醫學系 |
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