薑黃素引發人類大細胞肺癌細胞 NCI-H460 細胞凋亡的機轉研究; The Mechanisms of Curcumin-Induced Apoptosis of NCI-H460 Human Large Cell Carcinoma of Lung

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Title:	薑黃素引發人類大細胞肺癌細胞 NCI-H460 細胞凋亡的機轉研究;The Mechanisms of Curcumin-Induced Apoptosis of NCI-H460 Human Large Cell Carcinoma of Lung
Authors:	吳莘華;Shin-Hwar Wu
Contributors:	中國醫藥大學：臨床醫學研究所碩士班
Keywords:	細胞凋亡;細胞週期;薑黃素;肺癌;apoptosis;cell cycle;curcumin;lung neoplasms
Date:	2009-06-15
Issue Date:	2009-08-12 14:23:31 (UTC+8)
Abstract:	已陸續有報導薑黃素在抗癌上的效果。但薑黃素對於人類大細胞肺癌細胞 NCI-H460的作用機轉卻未被詳細探討過。本研究以薑黃素處理人類大細胞肺癌細胞 NCI-H460以評估其抗癌效果。我們以不同濃度的薑黃素對NCI-H460細胞作用不同的時間，其後再評估後續的細胞形態、存活率、蛋白質表現與mRNA 轉錄等的變化。結果顯示：隨著薑黃素濃度增高至20 μM以上， NCI-H460 細胞凋亡與死亡的比率也隨之上升。.薑黃素處理後，抗細胞凋亡的Bcl-2、XIAP和Bcl-xl蛋白表現量下降，促細胞凋亡的Bad和Bax 蛋白表現量增加。此外，活性氧化物 (reactive oxygen species,ROS) 與細胞質內鈣離子的濃度也在處理後上升。這些訊號導致粒腺體膜電位下降，後續激發了caspase 9 與 caspase 3的活化，最終產生細胞死於細胞凋亡的結果。另外，薑黃素的處理亦可導致Fas 蛋白質表現增加與caspase 8的活化，而經由所謂的外路徑 (extrinsic pathway) 引起細胞死於細胞凋亡。我們也分別以ROS 與caspase 8 抑制劑來阻礙細胞凋亡的訊息傳遞，結果發現在前述任一種抑制劑作用下，NCI-H460細胞的死亡率均明顯下降。這顯示了這些訊息傳導物質確實相當程度地介入了薑黃素所引發的細胞凋亡。薑黃素另外可導致 NCI-H460 細胞週期停滯於 G2/M 期，此舉可能是藉由降低 cyclin-depedent kinase 1 來達成的。總結來說，薑黃素對人類大細胞肺癌細胞 NCI-H460 可產生引發細胞凋亡或導致細胞週期停滯而達到抗癌的效果。我們認為它有潛力成為治療人類大細胞肺癌的藥物。 Reports about the anti-cancer activities of curcumin are accumulating. However, its effect on human large cell carcinoma NCI-H460 cells has never been scrutinized. In this study, we used curcumin to treat human non-small cell lung cancer cells (NCI-H460) to determine its anti-cancer activity. Various concentrations of curcumin were added to NCI-H460 cells for different durations in vitro and the subsequent changes in cell morphologies, viabilities, cell cycles, intracellular proteins and mRNA expressions were investigated. We found curcumin, when over 20 μM in concentration, induced NCI-H460 cell apoptosis and morphologic changes in a dose-dependent manner. After curcumin treatment, Bax and Bad were up-regulated, Bcl-2, Bcl-xL and XIAP were down-regulated. In addition, reactive oxygen species (ROS), cytoplasmic calcium and endoplasmic reticulum stress were increased in NCI-H460 cells after treatment with curcumin. These signals led to mitochondrial membrane potential decrease and culminated in caspase-3 activation. Apoptosis could also be induced through Fas-caspase-8 (extrinsic) pathway. The cell death induced by curcumin could be significantly reversed by adding ROS or caspase 8 inhibitors. NCI-H460 cells tended to be arrested at G2/M cell cycle stage after curcumin treatment. Down-regulation of cyclin-depedent kinase 1 by curcumin may be involved in the mechanism of such an arrest. In conclusion, curcumin exerts its anti-cancer effects on lung cancer NCI-H460 cells through apoptosis or cell cycle arrest. Curcumin is potentially an anti-cancer therapy for human large cell carcinoma of lung.
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