白楊素誘導GBM 8401腦神經膠質瘤癌細胞產生G2/M期停滯以及細胞凋亡經由caspase-非依賴型粒線體途徑

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Title:	白楊素誘導GBM 8401腦神經膠質瘤癌細胞產生G2/M期停滯以及細胞凋亡經由caspase-非依賴型粒線體途徑 Chrysin Induces Cell Cycle Arrest and Apoptosis via Caspase-independent Pathway in GBM 8401 Cells.
Authors:	林詩慧;Shih-Hui Lin
Contributors:	醫學院基礎醫學研究所
Keywords:	惡性腦瘤;白楊素;細胞凋亡;細胞週期;細胞轉移;GBM 8401;chrysin;apoptosis;cell cycle;migration;invasion
Date:	2010
Issue Date:	2010-09-29 12:13:37 (UTC+8)
Abstract:	神經膠質瘤是最難以治療的原發腫瘤之ㄧ。目前的治療法多為手術切除和化療以及放射線治療，但其效果都不盡理想。本實驗室的研究是著重於開發新的抗癌藥物。白楊素（5, 7-dihydroxyflavone），為類黃酮素的成分之一，其被研究出具有抗腫瘤，抗氧化，抗發炎的功效。許多研究指出，類黃酮素具有抗癌的效果；而類黃酮素可以從蜂膠、蜂蜜以及植物中被萃取出來。本篇研究結果顯示–白楊素能誘導人類腦神經膠質瘤細胞株產生細胞凋亡及形態改變，並且具備有劑量及時間的依存性。白楊素甚至能誘導腦癌細胞產生細胞週期G2/M 期的停滯。再者，DAPI 染色, DNA 膠體電泳法，彗星試驗，以及磷脂絲胺酸分析都顯示出白楊素能誘發細胞凋亡。更近一步地，我們證實了白楊素藉由活化活性氧化物質、使鈣離子增加，心磷脂氧化，以及導粒腺體膜電位下降的路徑來誘發細胞產生凋亡的現象。有趣的是，在凋亡蛋白與mRNA 表現部分，我們證實AIF 以及 Endo G 有大量表現，但Caspase-3, Caspase-8 以及 Caspase-9 的改變量卻很少。因此我們證實了在GBM 8401 模式中，白楊素引發腦癌細胞死亡的主要路徑是經由Caspase 非依賴性粒腺體途徑，並且具有時間的依存性。再者，使用ROS、鈣離子以及廣效性Caspase 抑制劑都能再次證實這個理論。總而言之，白楊素能誘發腦神經膠質瘤細胞GBM 8401 死亡是經由細胞凋亡以及細胞週期停滯。因此，在未來的研究上，白楊素或許可以成為一個新興的抗腦癌藥物。 The glioma is the most difficult to treat of primary tumor, has been difficult to manage after chemicaltherapy, radiotherapy and surgical. Our major focus on our laboratory is to develop and find a new anti-cancer drug for glioma treatment. Chrysin, a flavonoid which was extracted from propolis, honey and plants, has been reported to have anti-cancerous, anti-oxidative, and anti-inflammatory effects. Proplis is well known in Taiwan as a traditional Chinese medicine. The results indicated that chrysin induced morphological changes and cell death in human brain cancer GBM 8401 cells and these effects are in time- and dose-dependent manners. We also found that chrysin (Proplis extracts) caused G2/M phase arrest and apoptosis. Moreover, DAPI staining, DNA electrophoresis, Comet assay, and annexin?nⅤ?nalso showed that chrysin induced apoptosis. Furthermore, we suggest that chrysin promoted the levels of reactive oxygen species (ROS), NO and Ca2+ concentration, Cardiolipin oxidation, but decreased mitochondrial membrane potential in GBM 8401 cells. Interestingly, we are focused on the protein levels and mRNA expressions, AIF and Endo G were up-regulated but Caspase-3, Caspase-8 and Caspase-9 were changes a little. And we demonstrate that chrysin induced cell death via caspase-independent mitochondrial pathway which is involved in apoptosis from GBM 8401 cells after were incubated for different time periods. In addition, by adding ROS or Calaium inhibitor, cell death induced by chrysin could be significantly rose, but it could not be reversed by general caspase inhibitor. In conclusion, chrysin has anti-brain cancer effects on GBM 8401 cells through apoptosis and cell cycle. Thus, chrysin can be a new anti-cancer drug and used in clinical therapy.
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