臺灣博碩士論文加值系統

逐漸增加的證據報導骨髓衍生的內皮前驅細胞（endothelial progenitor cells, EPCs）調控血管新生、產後血管生成以及腫瘤轉移。一般認為瞭解天然產物的分子標的及藥理功能對於藥物發展是非常重要的。丹參酮IIA是從丹參（Salvia miltiorrhiza）分離出來的一個主要之二萜醌化合物，並且廣泛的使用於傳統中醫（traditional Chinese medicine, TCM）。雖然證據中指出丹參酮IIA能減少人類臍靜脈內皮細胞之血管新生作用，它在內皮前驅細胞的作用大部分卻是未知的。在本論文中，我們發現在無細胞毒性濃度下，丹參酮IIA以濃度依賴性而減少血管內皮生長因子（vascular endothelial growth factor, VEGF）所促進之人類內皮前驅細胞移行及血管生成。而在雞胚絨毛尿囊膜體內試驗中丹參酮IIA同時也抑制血管內皮生長因子誘導之血管新生。此外於小鼠動物模式中，我們觀察基質膠體 （matrigel plugs）也發現丹參酮IIA能抑制血管新生及內皮前驅細胞之表現。此外，丹參酮IIA阻斷血管內皮生長因子誘導之PLC、Akt及JNK磷酸化，而非p38及ERK活化。總結以上，我們的結果是首次驗證在體外及體內實驗中，丹參酮IIA減少內皮前驅細胞血管新生作用。丹參酮IIA顯示了在腫瘤抗血管新生療法及血管新生相關病理中之高度潛力。

Accumulating evidences report that bone marrow-derived endothelial progenitor cells (EPCs) regulate angiogenesis, postnatal neovascularization and tumor metastasis. It has been suggested that understanding the molecular targets and pharmacological functions of natural products is important for drug discovery. Tanshinone IIA is a major diterpene quinone compound isolated from Danshen (Salvia miltiorrhiza), and is widely used in traditional Chinese medicine (TCM). Although evidence indicates that tanshinone IIA reduces angiogenic function in human umbilical vein endothelial cells. However, the anti-angiogenic activity of tanshinone IIA on human EPCs has not been addressed. Here, we found that tanshinone IIA dramatically suppressed vascular endothelial growth factor (VEGF) promoted migration and tube formation of human EPCs without cytotoxic effects. Tanshinone IIA also markedly inhibits VEGF-induced angiogenesis in the chick embryo chorioallantoic membrane (CAM) model. Importantly, Tanshinone IIA significantly attenuated microvessel formation and the expression of specific EPCs marker in Matrigel plug-implanted mouse model. Mechanistic investigations demonstrated that tanshinone IIA inhibits EPCs angiogenesis through the PLC, Akt and JNK signaling pathways. Taken together, our report is the first to reveal that tanshinone IIA reduces EPC angiogenesis both in vitro and in vivo. Tanshinone IIA is a promising natural product worthy of further development for the treatment of cancer and other angiogenesis-related pathologies.

目次
第一章、前言 1
1.1 研究背景 1
1.2 研究目的 2
第二章、文獻探討 3
2.1 腫瘤轉移 3
2.2 血管新生與腫瘤轉移 6
2.3 血管新生相關因子 10
2.4 血管內皮生長因子 13
2.5 內皮前驅細胞 15
2.6 傳統醫學對腫瘤的認識 18
2.7 傳統醫學治療腫瘤的概況 22
2.8 瘀血與腫瘤的關聯 27
2.9 中藥丹參及其萃取物 30
第三章、材料與方法 35
3.1 實驗材料 35
3.1.1 實驗細胞株 35
3.1.2 實驗儀器 35
3.1.3 實驗試劑 36
3.2 實驗方法 38
3.2.1 細胞計數 38
3.2.2 細胞存活率分析 38
3.2.3 細胞毒性測定 39
3.2.4 西方墨點法 39
3.2.5 細胞移行分析 40
3.2.6 類血管生成試驗 40
3.2.7 雞胚絨毛尿囊膜模式 41
3.2.8 基質膠體實驗 41
3.2.9 免疫組織化學染色 42
3.2.10 血紅素蛋白分析 43
3.2.11 統計分析方法 43
第四章、結果 44
4.1 丹參酮IIA在人類內皮前驅細胞並無細胞毒性 44
4.2 丹參酮IIA抑制血管內皮生長因子誘導之內皮前驅細胞 移行及血管生成 46
4.3 丹參酮IIA抑制血管內皮生長因子誘導之內皮前驅細胞 PLCΓ及AKT活化 47
4.4 丹參酮IIA抑制血管內皮生長因子誘導之內皮前驅細胞 JNK活化而非ERK及P38 50
4.5 丹參酮IIA減少活體內實驗之血管新生作用 52
第五章、討論 55
第六章、結論 58
參考文獻 59

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