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系統識別號 U0026-0812200913430805
論文名稱(中文) 熊果酸於體內及體外抑制癌細胞增生及轉移活性之探討
論文名稱(英文) Ursolic acid inhibits the proliferation and metastasis of cancer cells in vivo and in vitro
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 95
學期 2
出版年 96
研究生(中文) 吳其玲
研究生(英文) Chi-Ling Wu
學號 s2694108
學位類別 碩士
語文別 英文
論文頁數 63頁
口試委員 口試委員-洪正路
口試委員-鄭瑞棠
指導教授-李益謙
中文關鍵字 增生  熊果酸    轉移 
英文關鍵字 ursolic acid  metastasis  cancer  proliferation 
學科別分類
中文摘要 熊果酸為一種五環三萜類化合物,廣泛分布於許多藥用及食用植物。目前已知熊果酸具有許多藥理活性,如抗病毒、抗菌、保肝、胰島素模擬、促進胰島素敏感性以及抗癌等作用。同時目前已知,熊果酸可透過許多機制達到抗癌作用,例如在體外抑制癌細胞增生以及細胞凋亡,像是人類肝癌細胞、人類胃癌細胞以及血癌細胞,然而,熊果酸於體內是否具有抗癌活性的研究證據則相當少。本研究針對參與癌症進展的幾個主要步驟,包括癌細胞的增生、轉移及血管新生探討熊果酸於體內及體外的抗癌活性。
  從MTT assay實驗結果得知,熊果酸於體外對於幾株癌細胞,包括路易士肺癌 (LLC)、人類大腸直腸癌(SW480)、人類非小細胞肺癌(A549)、小鼠黑色素瘤(B16-F10) 以及人類前列腺癌(PC-3)均具有細胞毒殺作用且和劑量呈現正相關。利用流式細胞儀分析A549以及LLC細胞的細胞週期,結果顯示兩株細胞在熊果酸的處理之下,分別在48以及24小時內均有subG1峰的產生,且和劑量及時間呈現正相關。DNA片段化洋菜膠電泳分析進及以DAPI染細胞核一步證實熊果酸會導致這兩株細胞的死亡是經由細胞凋亡的途徑。而在體內利用路易士肺癌細胞(LLC)打入C57BL/6小鼠背部下所誘發原位癌實驗亦可顯示熊果酸具有抑制腫瘤生長的活性, 而從投與熊果酸治療的小鼠腫瘤組織中也可觀察到其血管密度小於控制組,此實驗結果和於ex vivo中進行的大動脈環實驗結果顯示大鼠動脈環在處理熊果酸5或10 M後所產生的微脈管相較於控制組較少的結果一致。低劑量熊果酸(5或10 M)在體外亦可抑制A549以及B16-F10細胞的爬行。此外,利用小鼠黑色素癌細胞(B16-F10)打入C57BL/6小鼠的尾巴所誘導的體內腫瘤轉移模式也發現,不論從肉眼或以蘇木紫-伊紅染色法(HE stain)觀察小鼠肺部,均發現熊果酸可明顯的抑制小鼠黑色素癌細胞轉移到肺形成結節。
從以上結果得知,熊果酸於體內及體外均具有抗癌的活性,其機制主要是透過促進癌細胞的凋亡、抑制癌細胞的轉移以及抑制血管新生。
英文摘要 Ursolic acid (UA) is a pentacyclic triterpene acid found in many herbal medicines and edible plants. Previous studies have shown that UA exhibits several pharmacological activities including antiviral, antibacterial, hepatoprotective, insulin-mimetic, insulin- sensitizing and anticancer activities. It has also been suggested that US possesses anticancer activities through several mechanisms, including cell proliferation inhibition and apoptosis in many cancer cell lines, such as HepG2, SGC790 and HL-60 cells. However, little evidence that been directly presented for its anti-tumor activity in vivo. This study aims at investigating the anticancer activities of UA in vitro and in vivo based on the multistep cancer progression including cancer cell proliferation, metastasis and angiogenesis.
MTT assay shows that UA exhibits significant cytotoxicities against several cancer cell lines, including LLC (Lewis lung carcinoma), SW480 (human colon adenocarcinoma), A549 (human lung carcinoma), B16-F10 (murine melanoma) and PC-3 (human prostate carcinoma) in a dose-dependent manner. Flow cytometry analysis reveals that the subG1 phase in A549 and LLC cell population is increased by UA treatment within 48 hrs and 24 h in dose- and time-dependent manners. DNA fragmentation assay and DAPI staining of nucleus confirm that the cause of cytotoxicity and cell death shown by increased subG1 phase are due to apoptosis. In vivo animal model using LLC cells implanted into the flank of C57BL/6 mice shows that UA significantly suppresses tumor growth in situ. The tumor tissues of UA treatment group exhibit less vascular densities than that of control group. The blood vessel suppression of UA is echoed by the ex vivo aortic ring assay which shows that aortic ring treated with UA at the dose of 5 or 10 M form less microvessels than the control group. UA at lower dose (5 or 10 M) can also inhibits cell migration of A549 and B16-F10 cells in vitro, suggesting that UA may be in involved in anti-metastasis. Furthermore, in the in vivo metastasis assay using B16-F10 cells injected into the tail vein of C57BL/6 mice, UA severely reduces the number of metastasized tumor nodules in the lungs either by eye observation or HE staining.
These results suggest that UA exhibits anticancer and antitumor activities through many mechanisms including promoting apoptosis of cancer cells, antimetastaic activities and antiangiogenic activities both in vivo and in vitro.
論文目次 考試合格證明
Abstract………………………………………………………I
中文摘要……………………………………………………III
Index………………………………………………………VIII
Abbreviations………………………………………………IX

Introduction…………………………………………………1
I. Cancer……………………………………………………1
II. Cell cycle………………………………………………2
III. Apoptosis………………………………………………3
IV. Metastasis………………………………………………7
V. Angiogenesis………………………………………… 11
VI. Ursolic acid………………………………………… 13
VII. Aims……………………………………………………14

Materials and methods……………………………………15
Materials……………………………………………………15
Methods………………………………………………………19
1. Cell culture and drug treatment………………… 19
2. MTT assay……………………………………………… 19
3. In vitro cytotoxicity assay by crystal violet
staining………………………………………………… 20
4. Cell cycle analysis………………………………… 20
5. Annexin V and PI staining………………………… 21
6. Preparation of cell lysate…………………………21
7. Western blot analysis……………………………… 21
8. DAPI staining………………………………………… 22
9. DNA fragmentation assay…………………………… 22
10. In vivo antitumor studies…………………………23
11. Immunohistochemistry (IHC)……………………… 23
12. Ex vivo aortic ring sprouting assay……………24
13. In vitro wound healing assay…………………… 25
14. Boyden chamber-cell migration assay………… 25
15. Gelatin zymography………………………………… 26
16. In vivo metastasis assay………………………… 26
17. Statistical analysis……………………………… 26

Results………………………………………………………27
I. UA induced the death of cancer cells
in vitro …………………………………………………27
UA inhibited the proliferation of several
cancer cell lines in vitro…………………………27
UA induced the subG1 peak of A549 and LLC
cells…………………………………………………… 27
UA treatment led to the exposure of
phosphatidylserine (PS) at the outer plasma
membrane of A549………………………………………28
UA induced the activation of caspase-3 in
A549 cells………………………………………………29
Chromatin condensation and apoptotic body
formation were induced after treatment with
UA…………………………………………………………30
UA induced DNA fragmentation of A549 and LLC
cells…………………………………………………… 30
II. The antitumor activities of UA in vivo and ex
vivo………………………………………………………30
UA arrested the tumor growth in vivo……………31
UA inhibited the angiogenesis in tumors
induced by LLC cells in vivo…………………… 31
UA inhibited the formation of vascular
network in ex vivo aortic ring sprouting
assay……………………………………………………32
III. UA inhibited cancer cell migration and
metastasis in vitro and in vivo………………… 32
UA inhibited the migration of A549 and
B16-F10 cells in vitro…………………………… 32
MMP-9 activities of A549 and B16-10 cells
were suppressed by UA in vitro………………… 33
UA suppressed the metastatic nodule
formation in the lungs in vivo………………… 33
Discussion………………………………………………… 34
References………………………………………………… 38
Tables and Figures……………………………………… 48
Curriculum Vitae………………………………………… 63
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