臺灣博碩士論文加值系統

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.

目錄
目錄 ---------------------------------------------------------------------------------- I
圖目錄 ---------------------------------------------------------------------------------- V
致謝 ------------------------------------------------------------------------------------- XI
中文摘要 ------------------------------------------------------------------------------- X
英文摘要 ------------------------------------------------------------------------------- XI
縮寫略字表 ---------------------------------------------------------------------------- XII
第一章 前言 --------------------------------------------------------------------------- 1
第一節 研究背景 ------------------------------------------------------------------ 1
一、惡性腫瘤 -------------------------------------------------------------------- 1
二、腦瘤 -------------------------------------------------------------------------- 1
三、人類腦神經膠質瘤（Human Glioblastoma Multiforme） --------- 2
四、白楊素（Chrysin）與癌症 ---------------------------------------------- 3
第二節 文獻回顧 ------------------------------------------------------------------ 5
細胞死亡（Cell Death）的途徑 ---------------------------------------------- 5
第二章 材料與方法 ------------------------------------------------------------------ 8
第一節 實驗設計流程 ------------------------------------------------------------ 8
第二節 實驗材料 ------------------------------------------------------------------ 10
一、細胞株來源與細胞培養 -------------------------------------------------- 10
二、藥品試劑 -------------------------------------------------------------------- 11
三、儀器設備與器材 ----------------------------------------------------------- 14
第三節 實驗方法 ------------------------------------------------------------------ 15
一、配製中藥化合物－白楊素：Chrysin ----------------------------------- 15
二、細胞保存與細胞活化 ----------------------------------------------------- 15
II
三、細胞培養 -------------------------------------------------------------------- 16
四、型態（Morphology）測試 -----------------------------------------------
五、初步分析細胞內訊息的變化 --------------------------------------------
18
19
1. 存活率（Viability）分析 -------------------------------------------- 19
2. 活性氧化物質（Reactive Oxygen Species，ROS）分析 ------ 21
3. 鈣離子（Ca2+）分析 ------------------------------------------------- 23
4. 一氧化氮（NO）分析 ----------------------------------------------- 25
5. 粒腺體膜電位（Mitochondria Membrane Potential；ΔΨμ）
分析 ----------------------------------------------------------------------
27
6. 粒腺體膜氧化（Nonyl Acridine Orange，NAO）分析 -------- 29
7. 細胞週期（Cell Cycle）分析 -------------------------------------- 31
六、細胞凋亡測驗 -------------------------------------------------------------- 33
1. 彗星試驗（Comet Assay） ----------------------------------------- 33
2. DAPI 染色 -------------------------------------------------------------- 35
3. DNA 膠體電泳法（DNA Electrophoresis） --------------------- 36
4. 早期細胞凋亡（Early Apoptosis）分析 -------------------------- 38
5. Caspase-3, -9 活性分析 ----------------------------------------------- 41
七、西方墨點法（Western Blot） ------------------------------------------- 43
八、即時定量PCR（Quantitative PCR，QPCR） ----------------------- 49
九、免疫螢光染色（Immunofluorescence Staining） ------------------- 51
十、抑制劑分析 ---------------------------------------------------------------- 53
十一、轉移試驗 ---------------------------------------------------------------- 54
1. 細胞癒傷試驗（Wound Healing Assay） ------------------------ 54
2. 細胞轉移與穿透能力試驗（Transwell Migration and Invasion
Assay） -----------------------------------------------------------------
55
III
十二、統計與分析（Statistics and Analysis） ----------------------------- 57
第三章 實驗結果與討論 ------------------------------------------------------------ 58
第一節 白楊素對人類腦癌細胞（GBM 8401 與U87 MG）的型態之
影響 --------------------------------------------------------------------
58
第二節 白楊素對人類腦癌細胞（GBM 8401 與U87 MG）的存活率
之影響 ------------------------------------------------------------------
62
第三節 白楊素對人類腦癌細胞（GBM 8401）產生活性氧化物質
（Reactive Oxygen Species，ROS）的影響 ----------------------
67
第四節 白楊素對人類腦癌細胞（GBM 8401）產生鈣離子（Ca2+）
的影響 ------------------------------------------------------------------
69
第五節 白楊素對人類腦癌細胞（GBM 8401）產生一氧化氮（NO）
的影響 ------------------------------------------------------------------
71
第六節 白楊素對人類腦癌細胞（GBM 8401）對粒腺體膜電位
（Mitochondria Membrane Protention；ΔΨm）的影響 ---------
73
第七節 白楊素對人類腦癌細胞（GBM 8401）對粒腺體氧化程度的
影響 ---------------------------------------------------------------------
75
第八節 檢測白楊素對腦癌細胞的細胞週期（Cell Cycle）之影響 -- 77
第九節 白楊素對人類腦癌細胞 （GBM 8401 與U87 MG）的DNA
傷害（DNA Damage）的影響 ------------------------------------
79
1. 彗星試驗（Comet Assay） ---------------------------------------- 79
2. DAPI 染色（DAPI Stain） ---------------------------------------- 82
3. DNA 膠體電泳法（DNA Electrophoresis） -------------------- 86
第十節 白楊素對人類腦癌細胞（GBM 8401）早期細胞凋亡的影
響 ----------------------------------------------------------------------
88
第十一節 白楊素對腦癌細胞的（GBM 8401）的Caspase -3,-9 活
IV
性之影響 ----------------------------------------------------------- 90
第十二節 白楊素對腦癌細胞的（GBM 8401）的細胞凋亡、細胞週
期路徑相關蛋白活性之影響 ------------------------------------
91
第十三節 白楊素對腦癌細胞的（GBM 8401）的細胞凋亡路徑相關
蛋白位置之影響 ---------------------------------------------------
95
第十四節 白楊素對腦癌細胞的（GBM 8401）的 mRNA 表現量之
影響 ------------------------------------------------------------------ 97
第十五節 用抑制劑確認白楊素對腦癌細胞（GBM 8401）細胞凋亡
路徑之影響 --------------------------------------------------------- 98
第十六節 白楊素對腦癌細胞（GBM 8401）的細胞癒傷（Wound
Healing Assay）之影響 ------------------------------------------
105
第十七節 白楊素對腦癌細胞（GBM 8401）的細胞轉移與穿透能力
（Transwell Migration and Invasion Assay）之影響 -------
106
第四章 討論與結論 ------------------------------------------------------------------ 109
第五章 參考文獻 --------------------------------------------------------------------- 115

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