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系統識別號 U0026-0108201211102700
論文名稱(中文) 新穎組蛋白去乙醯酶抑制劑WJ-6K於肺癌治療之效果及機制探討
論文名稱(英文) Effects and mechanisms of novel histone deacetylase inhibitor WJ-6K on lung cancer cell growth and metastasis.
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 100
學期 2
出版年 101
研究生(中文) 陳美瑜
研究生(英文) Mei-Yu Chen
學號 s26994095
學位類別 碩士
語文別 英文
論文頁數 79頁
口試委員 指導教授-王憶卿
口試委員-林嬪嬪
口試委員-黃偉展
口試委員-王應然
中文關鍵字 肺癌  組蛋白去乙醯酶抑制劑  腫瘤生長  癌症轉移  動物模式 
英文關鍵字 lung cancer  HDAC inhibitor  anti-tumor growth  anti-tumor metastasis  xenograft 
學科別分類
中文摘要 研究背景:前人研究發現,相較於正常細胞,許多固體及血液腫瘤中,組蛋白去乙醯酶 (Histone deacetylases, HDACs) 常有過度表現或活性增加的情況,因此HDACs被認為是具潛力的癌症治療標靶。目前已發展的組蛋白去乙醯酶抑制劑已證實具有多種抑癌能力並且在臨床使用於血液腫瘤治療;然而,組蛋白去乙醯酶抑制劑對於固體腫瘤的治療效果仍須進一步研究。
研究目的:藉由人類肺癌細胞及動物實驗模式,評估新穎的組蛋白去乙醯酶抑制劑的抗癌能力。
研究方法及結果:本研究利用組蛋白去乙醯酶螢光活性實驗 (in vitro HDAC activity assay) 大量篩選了500多個化合物,並發現WJ-6K 具有和美國FDA 核准的臨床用藥SAHA相似甚至更好的HDAC抑制能力。WJ-6K屬於廣泛型組蛋白去乙醯酶抑制劑,並有效促使細胞中組蛋白及非組蛋白的乙醯化。WJ-6K對不同的人類肺癌細胞株具有顯著毒殺能力,但不影響正常的肺癌細胞。本研究進一步利用流式細胞儀 (Flow Cytometry) 及細胞免疫螢光染色 (Immunocytochemistry) 發現,WJ-6K會造成肺癌細胞株A549及CL1-5的細胞週期停滯在G2/M時期,並進一步走向細胞凋亡 (Apoptosis)。當WJ-6K與目前臨床治療肺癌的第一線化療藥cisplatin合併使用時,可以透過抑制DNA損傷修復機制 (DNA damage repair),進而對肺癌細胞的毒殺性有協同作用,並可逆轉癌細胞對cisplatin的抗藥性。本研究進一步利用A549異位移植腫瘤動物模式發現,活體給予WJ-6K可以有效抑制腫瘤生長,其抑制效果較相同劑量的SAHA更為顯著,且沒有明顯副作用的出現。此外,透過細胞侵略移動力實驗 (transwell invasion assay) 也發現,低劑量的WJ-6K可以顯著抑制A549細胞的侵略移動能力。本研究進一步建立癌症轉移動物模式並發現經過WJ-6K低劑量處理的A549細胞,其轉移至肺臟的能力顯著降低。
結論:細胞及動物實驗結果顯示,WJ-6K可以有效抑制肺癌腫瘤生長及轉移,為具潛力及臨床發展價值的肺癌治療藥物。對動物體內之藥物代謝及藥物動力學值得作進一步的探討。
英文摘要 Background: Overexpression and/or increased activity of histone deacetylases (HDACs) in hematologic and solid malignancies make HDACs a potential therapeutic target for cancer treatment. However, many HDAC inhibitors show serious adverse events in the course of treatment for solid tumors.
Purpose: To evaluate the antitumor effects and toxicity of novel HDAC inhibitors, several candidate compounds were examined by in vitro and in vivo models of human lung cancer.
Methodology/Results: HDAC inhibition was examined by in vitro HDAC activity assay and western blot of acetylated histone and non-histone proteins. The cytotoxicity effect was examined in five human lung cancer cell lines. The antiproliferatative mechanisms were investigated by flow cytometric cell cycle analysis, apoptosis assay, and repair gene expression assay in cells treated with HDAC inhibitor along or in combination with cisplatin. Mice with A549 tumor xenograft were used to evaluate effects on tumor growth and tumor metastasis. Over 500 candidate compounds were screened by in vitro HDAC activity assay to search for potent HDAC inhibitors. We found that novel HDAC inhibitor, WJ-6K showed HDAC activity inhibition ability better or comparable to FDA-approved HDAC inhibitor SAHA and led to increased HDAC target protein acetylation in lung cancer cells. WJ-6K showed significant cytotoxicity in various lung cancer cell lines without affecting normal lung cell IMR90 at the dose range examined. WJ-6K led to cancer cell death through induction of cell cycle G2/M arrest and mitochondria-mediated apoptosis. Combined treatment of WJ-6K and conventional chemotherapy agent, cisplatin showed synergistic cytotoxicity in lung cancer cells including the cisplatin-resistant cell line H1435 through impairment of DNA damage repair. We further confirmed that WJ-6K was more effective than SAHA in inhibition of tumor growth in A549 xenograft animal model without significant side effects. Using trans-well invasion assays, we found that WJ-6K inhibited cell invasion in A549 at non-cytotoxic doses. We further demonstrated that WJ-6K pre-treatment significantly suppressed A549 metastases to lungs by experimental metastasis assay in mice.
Conclusions: Our findings suggest that WJ-6K is a novel potent HDAC inhibitor which suppresses tumor growth and metastasis in lung cancer model, and can potentially be used for lung cancer therapy.
論文目次 Introduction 1
I. Lung Cancer
i. The epidemiology of lung cancer 1
ii. Treatments of NSCLC 1
II. Chromatin modification and histone deacetylases (HDACs)
i. Genetic and epigenetic alterations in cancer 3
ii. Histone deacetylases (HDACs) 4
III. HDACs as a target for cancer treatment
i. HDACs and cancer 5
ii. The molecular mechanism and classification of
HDAC inhibitors (HDACIs) 5
iii. HDACIs in current clinical use and clinical trials 6
iv. HDACIs combination therapy 6
v. HDACIs resistance 7
IV. Overview of apoptosis
i. Apoptosis 7
ii. Caspases (cysteine-dependent aspartate-specific proteases) 8
iii. BCL-2 family (B-cell lymphoma 2 family) 9
iv. Pathways of apoptosis 10
v. Apoptosis and cancer 11
V. DNA damage response
i. Reactive oxygen species (ROS) 11
ii. DNA damage and DNA repair 13
iii. The DNA damage response and cancer therapy 14
VI. Overview of cell cycle
i. Cell cycle 14
ii. Cell cycle and cancer 15
VII. Overview of metastasis
i. Metastasis and cancer 15
ii. Integrins and focal adhesion complex 16

Purposes 17
I. In cell models 17
II. In animal models 18

Materials and Methods 19
I. Materials
i. Cell lines 19
ii. WJ-6K 19
iii. Animal 19
II. Methods
i. HDAC activity assay 20
ii. Cell cytotoxicity assay/MTT assay 20
iii. Colony formation 21
iv. Analysis of cell cycle distribution 21
v. Early apoptosis detection/phosphatidylserine (PS) staining 21
vi. Western blot analysis 22
vii. RNA extraction and Real-time reverse-transcriptase
Polymerase chain reaction (RT-PCR) 22
viii. Trans-well invasion assay 23
ix. Immunofluorescence staining and confocal
microscopic analysis 23
x. Immunohistochemistry (IHC) assay 24
xi. Animal model-in vivo anti-cancer growth assay 24
xii. Animal model-in vivo combined treatment
anti-cancer growth assay 25
xiii. Animal model-in vivo anti-cancer metastasis assay 25
xiv. Drug combination analysis 26
xv. Statistical analysis 26

Results 27
I. Compound library screening by in vitro HDAC activity assay
for potent HDAC inhibitors 27
II. WJ-6K exerts HDAC inhibition activity by inducing cellular
HDAC target protein acetylation. 27
III. WJ-6K inhibits cell growth of lung cancer cell lines without
affecting normal lung cell line. 27
IV. WJ-6K inhibits lung cancer cell growth through induction of
cell cycle G2/M arrest and cell apoptosis. 28
V. WJ-6K efficiently inhibits tumor growth in vivo through
HDAC inhibition and induction of apoptosis .29
VI. WJ-6K has no apparent toxicity to animals at the
effective treatment regimen. 30
VII. WJ-6K shows a synergistic effect when combined with cisplatin
through impairment of DNA repair. 30
VIII. WJ-6K shows a synergistic anti-tumor growth effect when
combined with cisplatin in vivo without significant side effect. 32
IX. WJ-6K suppresses invasion ability of lung cancer cell line at
low-cytotoxic doses through inhibition of
focal adhesion complex. 33
X. WJ-6K inhibits cancer metastasis in vivo. 34
Discussion 35
References 40
Figures 45
Tables 68
Appendix 72
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