1,2,3,4-Tetrahydro-6,7-dimethyl-2- vinylquinoxaline對GBM8401腦癌細胞的毒殺 性和機轉探討

The Cytotoxicity of 1,2,3,4-Tetrahydro-6,7 -dimethyl-2-vinylquinoxaline on GBM8401 Cell Line and Its Signaling Transduction

白宜芝(Yi-Chih Pai)

指導教授 ： 張建國

高雄醫學大學/藥學院/藥學研究所/碩士(2009年)

摘要

1,2,3,4-Tetrahydro-6,7-dimethyl-2-vinylquinoxaline (YSC-A1) 為quinoxaline 衍生物的一種。YSC-A1是在鈀催化下，經由2-丁烯-1,4-二醇和4,5-二甲基-苯二胺環化而成。
在一些文獻已指出quinoxaline衍生物具有細胞毒殺活性。因此對於同為quinoxaline衍生物的YSC-A1，我們想要探討其是否對腦癌細胞GBM8401具有抗癌活性以及其調控機轉。在本實驗中可觀察到，YSC-A1對腦癌細胞GBM8401具毒殺性且呈現劑量依賴性。而YSC-A1藉由抑制Cyclin B, CDK1, Cdc25c與Aurora B表現量和增加Chk1與p21的表現量，可導致GBM8401細胞週期停滯在G2/M phase。且在MAPK蛋白質表現上，YSC-A1會增加磷酸化p38及JNK表現和抑制磷酸化ERK1/2表現。此外，YSC-A1會活化 caspases-3, -8進而使poly(ADP-ribose) polymerase (PARP) 產生裂解而造成DNA damage。
綜合以上的結果及討論，可以知YSC-A1會經由MAPK路徑造成細胞凋亡，且YSC-A1也調控細胞週期調控因子而使細胞週期停滯於G2/M期進而造成細胞死亡。

關鍵字

細胞週期 ； CDK1 ； MAPK ； GBM8401

並列摘要

1,2,3,4-Tetrahydro-6,7-dimethyl-2-vinylquinoxaline (YSC-A1), one of quinoxaline derivatives, wasformed by cyclization processes through tandem allylic substitution reaction between 4,5-dimethyl-1,2-
phenylenediamine and 2-butene-1,4-diol in the presence of a palladium catalyst. Several studies have shown that quinoxaline derivatives are usually cytotoxic. Therefore, we have attempted to determine the cytotoxicity of YSC-A1 and elucidated the underlying mechanism. In this study, we have investigated the anti-proliferative and apoptotic effects of YSC-A1 on human brain glioblastoma multiforme cell line (GBM8401). We found that YSC-A1 could inhibit cell growth in a dose-dependent manner while causing the arrest GBM8401 cells at G2/M phase of the cell cycle that correlated with decrease of Cyclin B, CDK1, Cdc25c, and Aurora B levels. We have also found that YSC-A1 treatment could increase p38 and JNK phosphorylation but decrease ERK1/2 phosphorylation. Furthermore, we observed features of apoptosis after YSC-A1 treatment: activation of caspases-3, -8, poly(ADP-ribose) polymerase (PARP) cleavage and DNA fragmentation. Taken together, our data indicated that the growth inhibition of YSC-A1 is highly related to cell cycle arrest at the G2/M phase and the induction of MAP kinase-mediated apoptosis in GBM8401 cells.

並列關鍵字

cell cycle ； CDK1 ； MAPKs ； GBM8401

參考文獻

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