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研究生:蔡源鍾
研究生(外文):Yuan-Chung Tsai
論文名稱:山奈酚治療肺癌以及作為放射增敏劑之探討
論文名稱(外文):The novel role of kaempferol as a potent radiosensitizer for human lung cancer cells
指導教授:姚俊旭姚俊旭引用關係
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:臨床醫學研究所碩士班
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:79
中文關鍵詞:山奈酚肺癌放射增敏劑凋亡
外文關鍵詞:KaempferolLung cancerRadiosensitizerApoptosis
相關次數:
  • 被引用被引用:0
  • 點閱點閱:34
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  • 下載下載:8
  • 收藏至我的研究室書目清單書目收藏:0
根據過去的研究報告指出,山奈酚可以誘發癌細胞凋亡,但是從沒有任何一篇報告探討過山奈酚與放射線之間的交互作用。因此本研究將以山奈酚合併放射治療來探討相關的機轉以及其訊息傳遞路徑。為了模擬臨床上的藥物測試,我們選用非小細胞肺癌A549作為這次實驗的主要細胞。在實驗中,我們利用劉式染色法觀察細胞凋亡的型態,利用MTT分析法測定細胞加入藥物的存活率。利用DAPI/TUNEL染色法以及流式細胞儀來定量細胞的凋亡率,利用西方墨點法驗證山奈酚誘導癌細胞凋亡是透過活化細胞凋亡的路徑。接著,在合併放射線的實驗我們藉由MTT測定法初步判定放射線毒殺細胞的能力以及合併藥物之後細胞的存活率。為了使放射線的效用達到最佳效果,我們利用細胞週期分析評估細胞週期的變化,由細胞群落分析來判定是否山奈酚具有放射線增敏的效果。最後,由西方墨點法的結果發現,照射完放射線之後,山奈酚會抑制PI3K以及ERK之蛋白表現。總結以上結果,山奈酚治療A549非小細胞肺癌會導致細胞凋亡、抑制肺癌細胞存活路徑、對放射線有增敏的作用、照射完放射線之後抑制PI3K以及ERK的蛋白表現,因此,我們相信山奈酚具有發展成為一個放射增敏劑的潛力。

In this present study, apoptotic morphology was observed by Liu’s staining, in which cell viability was assayed with the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The apoptosis rate was measured with DAPI/TUNEL and Annexin V/PI staining. Kaempferol activation apoptosis pathway was proved by Western blotting. In a combination experiment, radiation toxicity was determined using the MTT assay, the most suitable of radiation-exposured time was determined by a cell cycle analysis. Towards the end, colony formation assay was used to prove the synergism effect of kaempferol. The protein expression of PI3K and ERK were elucidated by Western blotting. Kaempferol that were combined with radiation exhibits a synergism effect on A549 cells, which inhibiting the PI3K and ERK protein expression concurrently after irradiation. Overall, the treatment of A549 cells with kaempferol resulted (i) induce cell apoptosis (ii) which inhibited the cell survival pathway (iii) enhancing the radiosensitivity. Based on these results, it was suggested that kaempferol possess the ability of becoming a radiosensitizer in the near future.

Catalog

1.Introduction………………………………………….……..1

1-1 Lung cancer……………………………………………...1
1-2 Kaempferol……………………………………………...5
1-3 Apoptosis………………………………………………..7
1-4 Radiation therapy………………………………………10
1-5 Object of study…………………………………………14

2. Materials and Methods ………………………..…………15

2-1 Materials………………………………………………..17
2-2 Cell culture……………………………………………..22
2-3 MTT assay……………………………………………...22
2-4 Liu’s staining…………………………………………...23
2-5 DAPI/ TUNEL staining………………………………...24
2-6 Annexin V/ PI assay……………………………………25
2-7 Cell cycle analysis……………………………………...25
2-8 Clonogenic assay……………………………………….26
2-9 Braford protein assay…………………………………..29
2-10 Western blotting………………………………………32
2-11 Statistical analysis…………………………………….33



3. Results………………………………………………...……34
3-1 Kaempferol results in a dose-dependent decrease on cell viability………………………………………………...34
3-2 Kaempferol induce cell apoptosis………...…………40
3-3 Kaempferol was up-regulation the expression level of BAX,
PARP, and caspase-7 proteins and down-regulation the expression level for PI3K, p-AKT and p-ERK proteins………………....………….………….….……...46
3-4 Kaempferol can enhance radiosensitivity proved by MTT assay…………………………………………………...48
3-5 Cell cycle of A549 cells after treating with kaempferol..51
3-6 Kaempferol can enhance radiosensitivity on A549 cell..57
4. Discussion………………………………………………….60
5. Conclusion………………...……………………………….65
6. References…………………….…………………………...66


Figure index

Figure 1-1: The chemical structure of kaempferol…………...……..6
Figure 1-2: The two main forms of apoptosis signal transduction
pathway………………………………………..……9
Figure 1-3: The monoplace of hyperbaric oxygen chamber……..…..12
Figure 1-4: A model of EGFR-mediated radioprotection………......13
Figure 2-1: Flow chart of study……………………….…………16
Figure 3-1: Effects of kaempferol on A549 cell morphology….…....35
Figure 3-2: Effects of kaempferol on A549 cell morphology
under the influence of Liu’s staining……………......36
Figure 3-3: The cell viability of A549 cells treated with
kaempferol…………………………………........…..37
Figure 3-4: The cell viability of HFL-1 cells treated with
kaempferol……………………………………….….38
Figure 3-5: Cell viability rate of the A549 lung cancer cells
compare with the HFL-1 lung cells………………...… 39
Figure 3-6: Kaempferol induced A549 cell lines apoptosis………...41
Figure 3-7: Kaempferol induce cell apoptosis………………...…..43
Figure 3-8: Kaempferol induce cell apoptosis………...……..……44
Figure 3-9: The proteins levels of Bax, PI3K, p-AKT, p-ERK,
PARP, caspase-7 and caspase-3 in A549 cells
treated with kaempferol……………………...……….47
Figure 3-10: Radiation effect on A549 cells viability………….…..49
Figure 3-11: Radiation effect on A549 cells viability……….....…..50
Figure 3-12: The cell cycle of A549 cells after treating with kaempferol……………………………..…….…..52
Figure 3-13: The cell cycle of A549 cells after treating with kaempferol…………………………...…….…..53
Figure 3-14: The cell cycle of A549 cells after treating with kaempferol……………………………….………54
Figure 3-15: The cell cycle of A549 cells after treating with kaempferol……………………………….………55
Figure 3-16: The cell cycle of A549 cells after treating with kaempferol……………………………………….56
Figure 3-17: The surviving fraction of A549 cells after
irradiation……………………………...………58
Figure 3-18: Pharmacologic inhibition of phosphor-ERK and
phosphor-PI3K signal transduction pathway by
kaempferol……………………………….…...…..59
Figure 4-1: The model of kaempferol activating apoptosis pathway in human lung cancer cells A549…………………….64

Table index

Table 1-1: Histological types of lung cancers………………….3
Table 1-2: Pie chart of the NSCLC subtypes……..……………4
Table 2-1: Monitor unit of relative radiation dose……...……..28
Table 2-2: Standard curves of quantitative proteins……..……30
Table 2-3: Solution of sample protein…………………….…..31
Table 3-1: Kaempferol induce cell apoptosis…………………45

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