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研究生:劉欣怡
研究生(外文):Hsin-I Liu
論文名稱:透過抗發炎、抗氧化及抗腫瘤促進作用評估硫辛酸在化學預防上可能扮演的角色
論文名稱(外文):The possible role of alpha-lipoic acid in chemoprevention through anti-inflammation, anti-oxidation, and anti-tumor promotion
指導教授:王應然王應然引用關係
指導教授(外文):Ying-Jan Wang
學位類別:碩士
校院名稱:國立成功大學
系所名稱:環境醫學研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:中文
論文頁數:81
中文關鍵詞:癌症化學預防二氫硫辛酸硫辛酸發炎反應腫瘤促進作用氧化性壓力癌症轉移
外文關鍵詞:tumor promotionoxidative stressmetastasisAlpha-lipoic acid (LA)inflammationcancer chemopreventiondihydrolipoic acid (DHLA)
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癌症的化學預防就是利用萃取天然物或人工合成的化合物去阻斷、回復或預防癌症的發展。近年來,許多流行病學及動物研究已發現,存在於飲食、藥草及植物中的微量化學物質具有相當多樣的藥理特性,有益於預防多種癌症的發生。硫辛酸(α-lipoic acid, LA)是細胞可自行少量產生的雙硫化合物,主要的作用為粒線體內pyruvate dehydrogenase的輔酶,為生物膜維持正常功能的組成要素,且是一種強力的抗氧化劑及自由基清除者。而LA的還原態二氫硫辛酸(dihydrolipoic acid, DHLA)在研究中更被發現較LA擁有更好的抗氧化能力。已知許多疾病成因皆與氧化性壓力的產生有關,如:老化、癌症、發炎等。發炎反應易導致免疫相關細胞的趨化作用,進而造成ROS的產生,導致氧化性傷害。而在多步驟的致癌過程中,氧化性壓力亦已被證實在各階段均扮演很重要的角色。雖然許多研究證實LA有助於許多氧化性壓力相關疾病的治療,但是對於LA是否具有癌症預防潛能的研究,無論在體內及體外實驗仍缺乏。
本研究試圖以體外實驗將小鼠巨噬細胞RAW264.7處理內毒素(lipopolysaccharide, LPS),誘發產生一氧化氮(nitric oxide, NO)和前列腺素E2(prostaglandin E2, PGE2),並以西方墨點法測定誘發型一氧化氮合成酶(inducible NO synthase, iNOS)及環氧酶(cyclooxygenase type-2, COX-2)的蛋白表現,評估個別加入LA及DHLA的抗發炎能力。體內實驗以ICR小鼠皮膚處理TPA模式,產生發炎反應及氧化性壓力(priming和/或activation)與誘發腫瘤形成,藉由評估水腫、上皮增厚及小鼠腫瘤發生率,驗證LA/DHLA抗發炎、抗氧化及抑制腫瘤促進作用的能力。並利用LLC-bearing mice實驗模式評估LA/DHLA抑制腫瘤生長及對抗肺轉移的能力。
結果顯示,LA及DHLA皆能有效抑制由LPS誘發RAW 264.7產生的NO及PGE2,西方墨點法則觀察到iNOS蛋白表現抑制,但COX-2蛋白表現卻明顯促進的情形。體內實驗則發現DHLA可對抗ICR小鼠重複處理TPA造成的發炎反應(白血球滲透(priming)及白血球的氧化性傷害(activation)),而達到抑制水腫及上皮增生的效果,LA則無抑制能力。皮膚前處理DHLA抑制ICR小鼠兩階段DMBA/TPA誘發產生腫瘤的實驗,顯示DHLA抗腫瘤促進作用的能力較Resveratrol好。以LLC-bearing mice實驗模式連續腹腔注射給藥33天顯示LA並無抑制腫瘤生長及對抗肺轉移的能力。
綜合上述結果,LA/DHLA在抗發炎、抗氧化及抗腫瘤促進作用方面有一定程度的效果,然而在抗腫瘤生長及抗轉移的能力方面並無顯著效果,因此,LA/DHLA在癌症化學預防上可能扮演的角色仍須更進一步的研究加以釐清。
Cancer chemoprevention is defined as interruption, recovery or prevention of cancer developing by natural occurring or synthetic compounds. In recent years, many epidemiological and animal studies have suggested that microchemicals present in the diet, herbs and plants with pharmacological properties are useful agents for the prevention of a wide variety of human cancers. Alpha-lipoic acid (LA) is a disulfide compound that is produced in small quantities in cells, and functions naturally as a co-enzyme in the pyruvate dehydrogenase. It is also a physiological constituent of biological membranes, an efficient antioxidant and a scavenger of free radicals. Dihydrolipoic acid (DHLA), formed by reduction of LA, has been shown to possess more antioxidant properties than does LA. Oxidative stress has been revealed to be related to several diseases such as aging, cancer and inflammation. Among these, reactive oxygen species(ROS)play a pivotal role in the process of inflammation and multiple step carcinogenesis. Several studies also showed that treatment of LA is beneficial for many diseases caused by oxidative damage. However, there are scanty data with respect to anti-tumorigenesis activity of LA.
In the present works, we conducted the in vitro anti-inflammatory study to assess the effects of LA/DHLA on nitric oxide (NO) and prostaglandin E2 (PGE2) generation in RAW264.7 macrophages stimulated by lipopolysaccharide (LPS). Expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase type-2 (COX-2) proteins were assayed by western blotting. The in vivo short-term anti-inflammatory, anti-oxidative and long-term anti-tumor promoting activities of LA/DHLA were evaluated by topical TPA application to ICR mouse skin with measurement of edema formation, epidermal thickness, and incidence of tumor-bearing mice. In addition, the potency of anti-tumor growth and anti-metastasis of LA were also analyzed by using Lewis lung carcinoma-bearing mice experimental model.
We have demonstrated that LA and DHLA strongly suppressed the NO and PGE2 release in LPS-treated RAW264.7 cells. Western blot showedt down-regulation of iNOS, but up-regulation of COX-2 expression after treated with LA and DHLA in LPS-treated cells. In in vivo studies, we found that DHLA but not LA significantly inhibited skin inflammation induced by double TPA application by decreasing the edema and epidermal hyperplasia formation. Inhibitory effects of tumor promotion showed that DHLA possess higher anti-tumor promotic ability than the resveratrol in DMBA-initiated ICR mice. However, LA shows no inhibition effects of tumor growth and lung metastasis in LLC-bearing mice experimental model.
In summary, the data presented here indicate that LA/DHLA possess significant effects in anti-inflammation, anti-oxidation and anti-tumor promotion. Whereas, no effects were found in anti-tumor growth and anti-metastasis. Thus, more studies are needed to further elucidate the role of LA/DHLA in cancer chemoprevention.
中文摘要 I
Abstract III
第一章、緒論 1
第二章、文獻回顧
第一節、硫辛酸簡介 2
第二節、氧化性壓力與疾病成因 2
第三節、硫辛酸的治療潛能及抗氧化研究 3
第四節、硫辛酸的副作用及毒性 5
第五節、一氧化氮與一氧化氮合成酶的角色 5
第六節、環氧化酵素與前列腺素的角色 7
第七節、小鼠皮膚重複處理TPA模式 8
第八節、化學致癌的三步驟 9
第九節、小鼠皮膚兩階段致癌模式 9
第十節、癌症的轉移 10
第三章、研究目的及重要性 11
第四章、研究架構 12
第一節、細胞實驗 13
第二節、動物實驗 14
第五章、研究材料及方法
第一節、研究材料
I.藥品試劑 17
II.常用儀器 18
III.常用溶液 19
第二節、研究方法
I.體外實驗(In Vitro)
(一)細胞解凍步驟 21
(二)細胞繼代培養步驟 21
(三)細胞冷凍步驟 22
(四)細胞計數 22
(五)Nitrite的測定與分析 23
(六)PGE2的測定與分析 24
(七)蛋白質電泳分析 25
(八)細胞存活率偵測分析(MTT assay)28
II. 體內實驗(In Vivo)
(一)小鼠皮膚重複處理TPA實驗 29
(二)小鼠皮膚兩階段致癌實驗 30
(三)LLC-bearing mice之腫瘤生長與肺轉移實驗 32
(四)石蠟切片(paraffin section)33
(五)蘇木紫伊紅染色(hematoxylin & eosin staining) 34
(六)統計分析 35
第六章、實驗結果
第一節、小鼠RAW264.7 macrophage cell line處理LPS誘發發炎相關因子過度表現,評估LA/DHLA抗發炎的能力
I.LA及DHLA可抑制由LPS誘發RAW264.7細胞產生的NO 36
II.LA及DHLA可抑制由LPS誘發RAW264.7細胞產生的PGE2 37
III. LA及DHLA對iNOS及COX-2表現的影響 37
IV. LA及DHLA不具有直接清除NO的能力 38
第二節、以小鼠皮膚重複處理TPA模式探討LA/DHLA抑制氧 化性壓力及抗發炎的能力
I. LA/DHLA對抗priming及activation作用的能力 39
第三節、以小鼠皮膚兩階段致癌模式驗證LA/DHLA對抗腫瘤生成的能力
I.促進過程小鼠體重變化情形及健康狀況 41
II.腫瘤生長的情形 41
第四節、以LLC-bearing mice實驗模式評估LA抑制腫瘤生長以及抗轉移的潛能
I.實驗過程小鼠體重變化情形及健康狀況 42
II.LA抑制腫瘤生長的情形 43
III.LA抑制肺轉移及影響存活時間的的結果 43
第七章、討論 45
第八章、結論與建議 51
參考文獻 52
附錄 61
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