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研究生:李維駿
研究生(外文):Wei-Jiunn
論文名稱:黃鹼素抗癌活性機制之研究
論文名稱(外文):Studies on the anti-cancer activity and mechanisms of flavone
指導教授:曾翠華曾翠華引用關係陳文貴陳文貴引用關係
指導教授(外文):Tsui-Hwa TsengWen-Kang Chen
學位類別:博士
校院名稱:中山醫學大學
系所名稱:生化暨生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:200
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類黃酮是一種多酚類化合物,為人類的完整飲食中的成分,普遍存在於開花植物中尤其是食用植物,在亞洲數千年的傳統醫藥中,許多植物及香料中所含有的類黃酮衍生物被發現可應用於疾病的預防與治療,經由篩選某些特定的食用植物及植物的組織或草藥,顯示其對健康的益處來自於其類黃酮的成分,在亞洲發生結腸癌、攝護腺癌以及乳癌的風險都較低,由於亞洲人對蔬菜、水果及茶葉的攝取量較西半球為高,因此提高了一個疑問,是否多攝取這類食品,透過類黃酮成分的保護效果,可作為天然的化學預防與抗癌試劑,而其中植物類黃酮最引人注意的報導在於其抗癌的作用,對類黃酮在抗癌活性的研究上,在in vitro的部份主要在探討其直接或間接對腫瘤細胞的作用,而研究發現類黃酮具有多樣化的抗癌活性,像是抑制細胞生長與激酶活性,誘導細胞凋亡與抑制基質金屬蛋白酶以及腫瘤侵犯的能力,此外某些的研究也曾經報導在in vivo中類黃酮會造成血管新生的損傷,而動物實驗的研究也顯示某些類黃酮具有抗癌的活性。
癌症的轉移是造成癌症死亡的主要原因,轉移的擴散是一個複雜的過程,包括不同的階段,包含腫瘤細胞由原位癌分離擴散、侵入淋巴及血液循環、吸附至遠端的內皮細胞並在此開始生長,而腫瘤細胞的遠端轉移能力受到腫瘤與宿主間交互作用的調控,尤其是血液中的癌細胞與微血管內皮細胞的交互作用,接著穩定的吸附並外滲出循環系統,這些都是在轉移生長中的關鍵階段,而且只有吸附於內皮細胞的腫瘤細胞能夠存活及增生,為了了解類黃酮在抑制腫瘤生長及轉移的機制,我們利用肝臟生長因子(HGF)誘導細胞侵犯的模式進行研究,在我們的初步研究中,我們自六種不同結構的類黃酮成分,包括黃鹼素(flavones)、黃酮醇(flavonols)、黃烷醇(flavanols)、黃烷酮(flavanones)、異黃酮(isoflavones)以及花青素(anthocyanidins)中,篩選特定的類黃酮化合物,研究其對於細胞毒性及HGF依賴性侵犯生長的影響,結果顯示在無細胞毒性劑量下,以黃鹼素的木犀草素(luteolin)對肝癌細胞HepG2的抗侵襲能力最強,而對乳癌細胞MDA-MB-231的抗侵襲能力則以黃鹼素的芹菜素(apigenin)最強。
黃鹼素是以黃烷酮為生物合成的先驅物,經由花青素/前花青素合成路徑(anthocyanidin/proanthocyanidin pathway)的分支點所產成的(附圖一),近來由於含有黃鹼素的食物在預防某些人類疾病的可能益處,而引起科學上及治療上的高度興趣,黃鹼素本身具有的生化與藥理活性對於人類健康的益處包括抗氧化、抗癌症形成、抗發炎、抗增生、抗血管新生且在飲食攝取上呈現無毒性或很低的毒性,流行病學及動物研究也顯示攝取高類黃酮飲食包括黃鹼素,與降低各種癌症、冠狀動脈心臟病,慢性發炎及骨質疏鬆的風險。
因為黃鹼素的生化活性與其結構有關,因此每個化合物都需要有系統的研究來評估個別的生物效用,此外比較分析各種不同種類的黃鹼素來測試最具抗癌活性的化合物是必要的,因此我們進一步的研究分子的機制來支持luteolin與apigenin抑制HGF相關的細胞侵犯與腫瘤轉移,在此我們證實在HepG2細胞中luteolin可以抑制HGF誘導的細胞發散(cell scattering)與細胞骨架改變(cytoskeleton change),luteolin也可抑制HGF所誘導的c-Met與ERK1/2以及Akt的磷酸化,而這些訊息路徑對於HGF相關的細胞侵犯是必須的,此外apigenin則能阻斷HGF誘導的Akt磷酸化以及β4 integrin的親和力,而抑制β4 integrin的功能則與減緩MDA-MB-231細胞與基質及內皮細胞吸附的能力,在in vitro中此吸附作用與HGF相關的侵犯作用有關,在裸鼠中則與癌細胞的肺部移生有關,而在雞胚胎中則與自發性的器官轉移有關,這些結果提供了對於黃鹼素中的luteolin與apigenin在抑制HGF相關的侵犯及轉移的機制,此外apigenin也會增加在許多基因轉錄調控上扮演重要角色的組蛋白3的乙醯化作用,因而誘導p21WAF1/CIP1的表現進而有意義的誘導細胞週期停滯與抑制乳癌腫瘤的生長。
因此植物中的黃鹼素在抗癌活性上的多樣性機制未來仍須進一步的研究,而某些日常飲食中以細胞表面訊息傳遞因子像是蛋白質酪胺酸激酶(protein tyrosine kinases)與焦點粘連激酶(focal adhesion kinases)以及腫瘤形成與轉移為影響目標的黃鹼素,似乎有希望成為抗癌的試劑,而進一步針對這些成分的生物活性在in vivo上的研究,對於發展以黃鹼素為基礎的抗癌治療策略是必要的,有鑑於近年來增加對黃鹼素與癌症的形成與發展間關係的興趣,而此重要的觀點很有可能證明其更廣泛的效用並吸引與刺激更深入的研究。

The flavonoids are polyphenolic compounds found as integral components of the human diet. They are universally present as constituents of flowering plants, particularly of food plants. Several plants and spices containing flavonoid derivatives have found application as disease preventive and therapeutic agents in traditional medicine in Asia for thousands of years. The selection of a particular food plant, plant tissue or herb for its potential health benefits appears to mirror its flavonoid composition. The much lower risk of colon, prostate and breast cancers in Asians, who consume more vegetables, fruits and tea than populations in the Western hemisphere do, raises the question of whether flavonoid components mediate the protective effects of diets rich in these foodstuffs by acting as natural chemopreventive and anticancer agents. An impressive body of information exists on the antitumor action of plantflavonoids. In vitro work has concentrated on the direct and indirect actions of flavonoids on tumor cells, and has found a variety of anticancer effects such as cell growth and kinase activity inhibition, apoptosis induction, suppression of the secretion of matrix metalloproteinases and of tumor invasive behavior. Furthermore, some studies have reported the impairment of in vivo angiogenesis by flavonoids. Experimental animal studies indicate that certain flavonoids possess antitumor activity.
Metastatic disease still accounts for most of cancer related deaths. Metastatic spreading is a complex process that comprises different phases, tumor cells detachment from the primary tumor, invasion of lymphatic or blood circulation, adhesion to endothelia at distant sites, and growth therein. The outgrowth at distant sites of tumor cells with metastatic potential is modulated by defined tumor–host interactions. In particular, the interaction of blood-borne cancer cells with microvascular endothelia, with subsequent stable adhesion and extravasation, is a critical step in metastatic growth, as only endothelium-attached tumor cells appear to be able to survive and proliferate. To gain insight into mechanisms underlying tumor growth and metastasis inhibition by flavonoids, we have employed the HGF-induced cell invasion model. In our preliminary study, we investigated the effect by selection of a particular six categories of flavonoids, including flavones, flavonols, flavanols, flavanones, flavanonols and isoflavones, on cytotoxicity and HGF-dependent invasive growth. Results show in non-cytotoxicity concentrations that the flavones, luteolin presents the most potent anti-invasion properties in hepatoma HepG2 cells as well as apigenin presents the most potent in MDA-MB-231 breast cancer cells.
Flavones are synthesized at a branch point of the anthocyanidin/proanthocyanidin pathway from flavanones as the direct biosynthetical precursor(attached graph 一). Currently, flavone attract considerable scientific and therapeutic interest because of the assumed beneficial effect of flavone-containing food in the prevention of some human diseases. Flavones themselves have biochemical and pharmacological activities which are beneficial for human health, including antioxidant, anticancerogenic, anti-inflammatory, antiproliferative, and antiangiogenic, and ingestion produces no or very little toxicity. Epidemiology and animal studies suggested that a high dietary intake of flavonoids, including flavones, may be linked to a reduced risk of several cancers, coronary heart disease, chronic inflammation, and osteoporosis.
Because the biochemical activities depend on the flavone structures, each compound needs to be studied systematically to assess its individual biological potency. Additionally, comparative analyses with various flavones from different subgroups are necessary to examine anticancer activities of the most potent compounds. Thus, we futher investigated the molecular mechanism behind luteolin and apigenin suppress HGF-mediated cell invasion and tumor metastasis. Here, we demonstrate that luteolin inhibited HGF-induced cell scattering and cytoskeleton change in HepG2 cells. Luteolin also suppressed the HGF-induced phosphorylation of c-Met as well as ERK1/2 and Akt, which is required for HGF-mediated cell invasion. In addition, apigenin blocks the HGF-induced Akt phosphorylation and β4 integrin avidity, and suppress β4 integrin function correlation with reduced cell-matrix and cell-endothelial cells adhesion in MDA-MB-231 cells, which is correlation with HGF-mediated invasion in vitro and lung colonization in nude mice as well as spontaneous organ metastasis in chick embryo. These results provide a plausible mechanism for flavones, luteolin and apigenin, inhibited of HGF-mediated invasion and metastasis. Moreover, apigenin also significantly induced cell cycle arrest and inhibited breast tumor growth by inducts p21WAF1/CIP1 expression through increase histone 3 acetylation, which is an important role in transcriptional regulation of several genes.
Thus, the various mechanisms underlying the potential anticancer action of plant flavonoids await further elucidation. Certain dietary flavones targeting cell surface signal transduction enzymes, such as protein tyrosine kinases and focal adhesion kinases, and the processes of tumorigenesis and metastasis appear to be promising candidates as anticancer agents. Further in vivo studies of these bioactive constituents is deemed necessary in order to develop flavone-based anticancer strategies. In view of the increasing interest in the association between flavones and cancer initiation and progression, this important field is likely to witness expanded effort and to attract and stimulate further vigorous investigations.

目   錄
縮寫表……….…..…..……………………………………….V
中文摘要…………………………………………………………1
英文摘要…………………………………………………………4
第一部份木犀草素抑制肝細胞生長因子誘導肝癌細胞侵犯之研究
壹、中文摘要………………………………………………… 8
貳、英文摘要………………………………………………… 9
參、緒論……………………………………………………… 10
肆、研究動機………………………………………………… 16
伍、實驗材料與方法………………………………………… 17
陸、結果……………………………………………………… 26
一、類黃酮對HepG2的細胞毒性影響………………………. 26
二、類黃酮對HGF誘導HepG2細胞轉移及侵犯的影響……… 26
三、Luteolin對HGF子誘導HepG2細胞發散及細胞骨
架改變之影響.................................. 26
四、Luteolin對HGF誘導Met磷酸化之影響………………… 27
五、Luteolin對HGF活化HepG2細胞訊息路徑之影響……… 27
六、Luteolin經由抑制ERKs與Akt的訊息路徑抑制HGF
誘導的侵犯作用………………………………………… 28
柒、討論……………………………………………………… 29
捌、參考文獻………………………………………………… 33
玖、圖表與說明……………………………………………… 41
第二部份 芹菜素抑制肝臟生長因子促進乳癌轉移機制之研究
以及經由調控組蛋白乙醯化作用誘導p21表現
抑制MDA-MB-231乳癌細胞的增生
與減緩裸鼠的乳房腫瘤生長之研究
壹、中文摘要…………………………………………………… 53
貳、英文摘要…………………………………………………… 55
參、緒論………………………………………………………… 57
肆、研究動機…………………………………………………… 68
伍、實驗材料與方法…………………………………………… 70
陸、結果………………………………………………………… 88
一、各種類黃酮衍生物對乳癌細胞的細胞毒性分析………… 88
二、各種類黃酮衍生物對HGF誘導乳癌
細胞轉移及侵犯的影響…………………………………… 88
三、Apigenin結構類似物對MDA-MB-231乳癌細胞
的細胞毒性分析…………………………………………… 88
四、Apigenin與結構類似物對HGF誘導乳癌細胞
轉移及侵犯的影響………………………………………… 89
五、Apigenin對HGF誘導乳癌細胞與轉移
及侵犯有關現象的影響…………………………………… 89
(A) Apigenin對HGF誘導乳癌細胞轉移的影響………………….89
(B) Apigenin對HGF誘導乳癌細胞移動、增生
及發散能力的影響………………………………………… 89
(C) Apigenin對HGF誘導乳癌細胞侵犯的影響………………. 90
六、Apigenin對HGF活化c-Met之影響………………………… 90
七、Apigenin對HGF活化MDA-MB-231
細胞訊息傳導路徑之影響………………………………… 91
八、Apigenin對HGF活化MDA-MB-231
細胞訊息傳導路徑之影響………………………………… 91
九、Apigenin經由抑Akt的活化抑制HGF
子誘導的侵犯作用………………………………………… 92
十、HGF對osteopontin(OPN)表現的影響…………………. 92
十一、HGF對NFκB轉錄活性以及對MMPs
與MMPs inhibitor-TIMP-1, -2與uPA的蛋白質
表現及活化的影響……………………………………… 93
十二、HGF對E-cadherin表現的影響…………………………. 94
十三、Apigenin對HGF刺激細胞黏附作用之影響……………. 94
十四、Apigenin經由影響PI3-K減少β4 integrin的吸附及親和
力抑制HGF誘導的侵犯作用……………………………. 94
十五、Apigenin在裸鼠中對HGF誘導乳癌細胞產生肺部
移生的影響.................................... 96
十六、Apigenin在雞胚胎中對HGF促進乳癌細胞產生自發性
血管內滲及器官轉移的影響…………………………… 97
十七、Apigenin抑制MDA-MB-231乳癌細胞的生長…………… 98
十八、Apigenin經由引起細胞停滯於G2/GM期而抑制
MDA-MB-231生長而不是誘導細胞凋亡………………… 99
十九、Apigenin經由調控細胞週期蛋白的表現影響細胞週期. 99
二十、Apigenin對MDA-MB-231細胞非固著依賴性生長
(anchorage-independent growth)的影響…………… 99
二十一、Apigenin對組蛋白乙醯化的影響……..…………… 100
二十二、Apigenin抑制皮下轉殖MDA-MD-231乳癌細胞
在裸鼠中的腫瘤生長…………………….......... 100
二十三、Apigenin對裸鼠乳房腫瘤中MDA-MB-231細胞
有絲分裂的影響……………………………………… 101
二十四、Apigenin對裸鼠乳房腫瘤中組蛋白乙醯化
與cyclin A、B及p21表現的影響……………….... 101
柒、討論………………………………………………………… 103
捌、參考文獻…………………………………………………… 111
玖、圖表與說明………………………………………………… 128
拾、補充數據…………………………………………………… 188
Supplementary S1: quercetin經由ERK與JNK的路徑誘導
細胞凋亡以及增加組蛋白3的乙醯化………........... 188
Supplementary S2: quercetin抑制HDAC的活性
非依賴ERK與JNK的路徑……………………............ 189
Supplementary S3: quercetin經由ERK與JNK的路徑
增加HAT的活性……………………………………....... 190
Supplementary S4: apigenin對HDAC活性的影響…………… 191
Supplementary S5: apigenin對HAT活性的影響……………. 192
附圖……………………………………………………………… 193
已發表論文……………………………………………………… 200

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