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研究生:劉鳳樟
研究生(外文):Fon-Chang Liu
論文名稱:探討甘露飲與樟芝萃取物抑制血癌生長、移行與促進分化之相關分子機制:一項體內及體外試驗
論文名稱(外文):Exploration of the molecular mechanisms of Gan-Lu-Yin and Antrodia cinnamomea extracts on cellular proliferation, migration and differentiation of WEHI-3 cells : an in vitro and in vivo study
指導教授:吳介信吳介信引用關係
學位類別:博士
校院名稱:中國醫藥大學
系所名稱:藥學系博士班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:120
中文關鍵詞:甘露飲血管新生中國傳統醫學複方WEHI-3細胞移行增生抗白血病樟芝指標成分
外文關鍵詞:Gan-Lu-Yinantiangiogenictraditional chinese medicine formulaWEHI-3 cellsmigrationproliferationantileukemicAntrodia cinnamomeamarker components
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本研究的目的是探討中國傳統中草藥複方甘露飲(GLY)乙醇萃取物對WEHI-3細胞是否有影響增生、移行和分化的作用以及對WEHI-3細胞在BALB/c小鼠產生的腫瘤是否具有抗腫瘤作用。結果發現GLY會顯著減少WEHI-3細胞增生、移行及誘導分化。WEHI-3細胞處理GLY會使磷酸化的FAK、Akt、ERK1/2和Rb的蛋白質表現下降,而使p21的表現增加。細胞週期分析的結果也顯示GLY能顯著誘導G1期阻滯,並減少S期的情形。此外實驗結果也指出GLY會使MMP-2、MMP-9的蛋白質表現和活性的降低。GLY也減少WEHI-3白血病細胞浸潤到肝臟、脾臟和抑制腫瘤生長。因此GLY的抑制機制部分是通過抑制WEHI-3細胞中磷酸化的FAK、Akt和ERK的表現進而對腫瘤的生長產生抑制作用。在臨床應用中GLY可能會提供一個有潛力的抗白血病的方法。
此外我們也探討樟芝乙醇提取物(EEAC)是否會影響WEHI-3細胞的增生和移行及對WEHI-3細胞在BALB/c小鼠產生的腫瘤是否有抗腫瘤作用。結果顯示EEAC會抑制WEHI-3細胞的增生,而利用流式細胞儀分析細胞週期,發現EEAC會導致細胞分佈累積在G0/G1和G2/M期。由
Transwell assay發現EEAC顯著降低WEHI-3細胞的移行。在蛋白質表
現方面,EEAC明顯降低WEHI-3細胞中MMP-9蛋白和活性的表現。另外
磷酸化的Akt、ERK1/2蛋白表現也有所下降,卻相反增加p21和p27的表現。在體內腫瘤模式中,EEAC減少WEHI-3細胞進入肝臟和脾臟的浸潤並減少腫瘤的生長。其他活性化合物,如cordycepin和zhankuic acid A已被證明會減少MMP-9、cyclin E、cyclin D1的表現和增加p21、p27的表現。這個研究探討了EEAC減少WEHI-3細胞的體外增生和移行的機制以及EEAC減少WEHI-3細胞進入體內肝、脾的浸潤能力,在未來的抗白血病治療策略中,樟芝治療血癌被證明可能是有潛力的。


The aim of this study was to explore the antitumor effect of Gan-Lu-Yin (GLY), a traditional Chinese herbal formula on leukemia. Ethanolic extract of GLY was applied to evaluate its regulatory mechanisms on proliferation, migration and differentiation of WEHI-3 leukemic cells as well as antitumor effect on BALB/c mice model. The results showed that GLY markedly reduced cell proliferation and migration whereas induced differentiation of WEHI-3 cells. The expression level of phosphorylated FAK, Akt, ERK1/2 and Rb was decreased while p21 expression level was increased in WEHI-3 treated with GLY. The results of cell cycle analysis revealed that GLY treatment could markedly induce G1 phase arrest and decrease cell population in S phase. Moreover, experimental results demonstrated that GLY decreased the protein expression level and enzyme activity of MMP-2 and MMP-9. GLY treatment also reduced WEHI-3 leukemic infiltration to liver, spleen and tumor growth in animal model. Accordingly, GLY demonstrated an inhibitory effect on tumor growth with a regulatory mechanism partially through inhibiting FAK, Akt and ERK expression in WEHI-3 cells. GLY may provide a promising antileukemic approach in the clinical application.
Moreover, we also aimed to explore whether the ethanolic extract of Antrodia cinnamomea (EEAC), a medicinal mushroom from Taiwan, could affect the proliferation and migration of WEHI-3 cells in vitro. And also explore the antitumor effects of EEAC in BALB/c mice engrafted with WEHI-3 cells. Our results showed that EEAC inhibited the proliferation of WEHI-3 cells, resulting in the accumulation of cell in G0/G1 and G2/M phases, as determined by flow cytometry. Moreover, EEAC markedly reduced the migration of WEHI-3 cells, as determined by a transwell assay. Treatment of WEHI-3 cells with EEAC also decreased MMP-9 protein expression level and enzyme activity as well as the protein levels of p-Akt, p-ERK1/2 , whereas the expression level of p21 and p27 was increased. Furthermore, in our in vivo model, EEAC treatment reduced the infiltration of WEHI-3 cells into the liver and spleens and decreased tumor growth. Other bioactive compounds, such as cordycepin and zhankuic acid A, have been demonstrated to reduce the expression level of MMP-9, cyclin E, cyclin D1 and to increase the expression of p21 and p27. To sum up, this study was to investigate the mechanisms by which EEAC can reduce the proliferation and migration of WEHI-3 cells in vitro, as well as the ability of EEAC to reduced infiltration of WEHI-3 cells into the liver and spleen in vivo. The results suggest that EEAC can be developed as a potential candidate for antileukemic therapies.


目錄-------------------------------------------------------I
表目錄----------------------------------------------------II
圖目錄----------------------------------------------------IV
中文摘要--------------------------------------------------VI
英文摘要------------------------------------------------VIII
第一章 緒論------------------------------------------------1
第二章 總論------------------------------------------------4
第一節 甘露飲與樟芝之文獻考察----------------------------4
第二節 白血病簡介----------------------------------------7
第三節 細胞週期的調控-----------------------------------14
第四節 研究目的-----------------------------------------18
第三章 研究材料和方法-------------------------------------19
第一節 實驗設計-----------------------------------------19
第二節 研究材料-----------------------------------------20
第三節 實驗方法-----------------------------------------33
第四節 統計方法------------------------------------------43
第四章 結果-----------------------------------------------44
第五章 討論-----------------------------------------------54
第六章 結論-----------------------------------------------66
參考文獻-------------------------------------------------109


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