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標題: | 評估cytopiloyne aglycone在TS/A乳腺癌荷瘤小鼠的抗腫瘤效果與機制 Anti-tumor effect and mechanism of cytopiloyne aglycone in TS/A mammary gland tumor-bearing mice |
作者: | Kai-Wei Chen 陳凱偉 |
指導教授: | 楊文欽(Wen-Chin Yang) |
關鍵字: | 抗癌天然物,大花咸豐草,咸豐草聚乙炔去糖化合物,抗細胞增生與細胞凋亡,TS/A乳腺癌荷瘤小鼠,免疫組織染色,骨髓衍生抑制細胞, Anti-cancer natural products,Bidens pilosa,Cytopiloyne aglycone,Anti-proliferation and apoptosis,TS/A tumor-bearing mice,Immunohistochemical staining,Myeloid-Derived Suppressor Cells (MDSC), |
出版年 : | 2010 |
學位: | 碩士 |
摘要: | 乳癌是全球女性主要致死的惡性腫瘤,在過去25年來,約70 %的抗癌藥物來自天然物或其衍生物。依賴現有抗癌化學藥物常引發乳癌細胞對化學藥物產生抗性,以及新型抗癌化合物的開發作為組合性治療有助於乳癌的治療。因此找尋不同抗癌機制的藥物有其必要性。先前的研究發現大花咸豐草的萃取物具有抗癌活性。大花咸豐草可作為食物或民俗草藥使用,可治療許多疾病。我們與其他實驗室發現,大花咸豐草中有一個咸豐草聚乙炔去糖化合物 (cytopiloyne aglycone,CPA),具有抑制血管新生的生物活性。本論文中,我們首先證實CPA會隨著濃度增加,顯著地減少三種乳腺癌細胞 (TS/A、MCF-7和MDA-MB-231)的細胞存活率,其IC50值分別是3.12、3.37 和 3.56 μg/ml。顯示CPA對於乳癌細胞有良好的抑制生長能力,而且此抑制與雌激素的作用無關。進一步探討CPA的抗癌作用發現,低劑量CPA具有抑制細胞增生的能力,並且其抑制作用是長時間且癌細胞無法回復、消除,高劑量CPA會隨時間增加而導致癌細胞的死亡。流式細胞儀的分析顯示,CPA能引發TS/A乳癌細胞進行細胞凋亡,並且活化caspase 3/7的活性,造成TS/A乳癌細胞的死亡。利用TS/A乳腺癌荷瘤小鼠為動物模式,來評估CPA的抗腫瘤藥效。經給予TS/A荷瘤小鼠PTX和不同濃度的CPA,我們發現小鼠的腫瘤大小、重量都顯著地受到抑制,而小鼠本身並無出現嚴重的藥物毒性。免疫組織染色方式也證實,相較於控制組,CPA可抑制腫瘤細胞增生,促進腫瘤細胞凋亡,並且可以增加荷瘤小鼠的存活率。CPA在活體內的作用與體外細胞的作用一致。我們也發現PTX或CPA處理的荷瘤小鼠中,其骨髓與脾臟內的骨髓衍生抑制細胞 (MDSC)數量比控制組少,這結果顯示MDSC沒有上升可能是因為CPA抑制腫瘤細胞的生長和促進死亡,使得腫瘤誘發MDSC的能力下降所致。所有結果證明CPA在體內與體外都具有抑制乳腺癌細胞的能力,此一抑制作用可能是透過抑制細胞增生和促進癌細胞凋亡之途徑。 Breast cancer is a leading cause of death in women worldwide. For the past 25 years, 70 % of anticancer drugs have been developed from natural products or their derivatives. However, a major obstacle to a successful cancer therapy is the problems of drug resistance in cancer patients. Therefore, there is a need to seek new anti-cancer drugs with different mechanisms. Bidens pilosa is commonly used as a food or folk medicines for different diseases. We and other groups have identified cytopiloyne aglycone (CPA) from B. pilosa. CPA was reported to inhibit angiogenesis in human umbilical vein endothelial cells (HUVEC). However, the anti-tumor effects and mechanisms of CPA are poorly understood. In this study, we first investigated the effect of CPA on the cell growth of TS/A, MCF-7 and MDA-MB-231 cells. We found that CPA inhibited tumor cell growth in a dose dependent manner. The IC50 value for TS/A, MCF-7 and MDA-MB-231 cells were 3.12, 3.37 and 3.56 μg/ml, respectively. Furthermore, low dose of CPA inhibited TS/A cell proliferation and the effect on anti-proliferation was persistent and irreversible. High dose of CPA have cell cytotoxity to induce apoptosis of TS/A cells, as revealed by induce the caspase 3/7 activity in flow-cytometer data. We assessed anti-tumor effect of CPA in TS/A tumor-bearing BALB/c mice. We found that CPA treatment at 0.02, 0.1, 0.5 mg/kg suppressed the growth of TS/A tumors compared with control group mice, as evidenced by tumor size and mass via 24 days treatment period. And mice did not show serious symptoms of toxicity. The immunohistochemical staining results showed that the tumors from CPA-treated mice exhibited reduced cell proliferation and increased apoptosis compared with tumor from control group mice. Finally, the survival rate of any CPA-treated groups was prolonged significantly. The MDSC of bone marrow and spleen from PTX and CPA-treated mice were reduced. In conclusion, CPA had the effect of anti-tumor in breast cancer both in-vitro and in-vivo with reduced cell proliferation and induced cell apoptosis. There studies of CPA for chemotherapy medicine against breast cancer are thus warranted. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22796 |
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顯示於系所單位: | 動物學研究所 |
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