Plumbagin對人類黑色素細胞癌之作用機制探討

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Title:	Plumbagin對人類黑色素細胞癌之作用機制探討 The molecular mechanism of plumbagin in human melanoma A375.S2 cells
Authors:	宋淑嬌 Shu-Chiao Sung
Contributors:	郭柏麟嘉南藥理科技大學：化妝品科技研究所
Keywords:	反應性活性氧黑色素細胞癌細胞凋亡 ROS Melanoma Apoptosis
Date:	2007
Issue Date:	2008-12-03 11:17:37 (UTC+8)
Abstract:	Plumbagin 已被研究對有抗菌、抗粥狀動脈硬化活性，而plumbagin 在抗癌方面不論在體內及體外的實驗中，也被證實出具有抗癌、抗增生的效果。本研究以plumbagin 為研究主題，分析在黑色素細胞癌A375.S2 的抗細胞增生活性及相關機轉。研究結果顯示，plumbagin 可以藉由停止細胞週期於S-G2/M 期並誘發細胞凋亡而有效的抑制A375.S2 細胞增生。在細胞週期調控方面，plumbagin 可以增加p21(WAF1)的表現，降低Cyclin B1、Cyclin A、Cdc2 和Cdc25C的表現，並同時增加Cdc2 和Cdc25C 的磷酸化作用。透過上述機制，plumbagin 會促使A375.S2 細胞細胞週期停滯於S-G2/M 期。而粒線體細胞凋亡路徑方面，plumbagin 其作用包括增加Bax 和Bak 的表現，並同時降低Bcl-2 的量，進而改變Bax/ Bcl-2 的比例，以及caspase-9活化。另外，plumbagin 在A375.S2 細胞中發現會誘導產生大量超氧陰離子(O2.-) 及過氧化氫(H2O2) 自由基的累積，以及榖胱甘肽(Glutathione)的耗損，造成細胞的氧化壓力。並利用catalase 和vitaminC 抑制ROS 產生可明顯的抑制plumbagin 所誘導的細胞凋亡。Pumbagin 可以在不影響ASK1，JNK1/2 和ERK1/2 總蛋白質量的情況增加磷酸化ASK1，JNK1/2 和ERK1/2 的活化。相對的，plumbagin對於p38 的活化則無明顯的影響。利用JNK1/2 專一性抑制劑IVSP600125 及ERK1/2 專一性抑制劑PD98059 阻斷JNK1/2 和ERK1/2的活性時則可發現plumbagin 所誘導的細胞凋亡也會受到抑制，因此確認plumbagin 是透過JNK1/2 和ERK1/2 的活化而造成細胞凋亡。最後利用nude mice 的實驗模式也確認plumbagin 在in vivo 的條件下，也能有效的誘導A375.S2 細胞進行細胞凋亡，進而抑制A375.S2細胞的生長。經由此實驗可證實，plumbagin 是透過ROS 和JNK1/2的機轉而誘導細胞凋亡，達到抗癌的效果。 This study is the first to investigate the anticancer effect of plumbagin in human melanoma A375.S2 cells. Plumabagin exhibited effective cell growth inhibition by inducing cancer cells to undergo S-G2/M phase arrest and apoptosis. Further investigation revealed that plumbagin’s inhibition of cell growth was also evident in a nude mice model. Blockade of cell cycle was associated with increased levels of p21, and reduced amounts of cyclinB1, cyclinA, cdc2 and cdc25C. Plumbagin also enhanced the levels of inactivated phosphorylated cdc2 and cdc25C. Plumbagin triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in caspase-9 activation. We also found the generation of ROS is a critical mediator in plumbagin-induced cell growth inhibition. Antioxidants vitamin C and catalase significantly decreased apoptosis. In addition, plumbagin also increased the activation of ASK and then enhanced the phosphorylation of JNK and ERK1/2, but not p38. Moreover, blocking ERK and JNK by specific inhibitors suppressed plumbagin-induced apoptosis. Taken together, these results imply a critical role for ROS and JNK in the plumbagin’s anticancer activity.
Relation:	校內校外均不公開
Appears in Collections:	[Dept. of Cosmetic Science and institute of cosmetic science] Dissertations and Theses

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