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標題: 探討天然飲食中生物活性成分對離體中誘導細胞 凋亡與活體中抗腫瘤的研究
Investigations for induction of apoptosis in vitro and antitumor activity in vivo of the bioactive components in natural diatry
作者: 陳念谷
Chen, Nian-Gu
關鍵字: AITC;烯丙基異硫氰酸酯;GBM 8401;EGCG;TSGH-8301;HSP27;人類腦惡性膠質瘤;表沒食子兒茶素;沒食子酸酯;台灣特定人類膀胱癌;熱休克蛋白27
出版社: 獸醫學系暨研究所
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飲食與癌症治療息息相關,近年研究顯示適當的飲食可以降低癌症的發生率,這些天然飲食中的活性成分,可分為油溶性與水溶性兩類,本文第一部分談討油溶性成分烯丙基異硫氰酸酯 (Allyl isothiocyanate, AITC) 透過粒線體依賴性路徑引發人類腦惡性膠質瘤GBM 8401細胞產生G2/M期停滯及細胞凋亡。第二部分利用蛋白質體學研究水溶性成分表沒食子兒茶素沒食子酸酯 (Epigallocatechin gallate; EGCG) 挑起台灣特定人類膀胱癌TSGH-8301細胞產生的細胞凋亡。
第一部分:異硫氰酸酯 (isothiocyanates; ITCs) 以硫代葡萄糖苷 (glucosinolates)形式存在於不同的十字花科 (cruciferous)蔬菜中。其中烯丙基異硫氰酸酯 (allyl isothiocyanate; AITC) 是一種常見的自然產生異硫氰酸酯 (ITCs)。最近的研究顯示AITC在離體試驗 (in vitro)中可抑制人類血癌HL-60細胞、膀胱癌UM-UC-3細胞和結腸癌HT-29細胞的存活率。本研究中,我們發現AITC能夠劑量依賴性明顯地減低人類腦惡性膠質瘤GBM 8401細胞的增殖和存活率,以24小時處理其最大抑制50%濃度 (the half maximal inhibitory concentration; IC50)為9.25±0.69 μM。在細胞週期分佈分析也顯示,AITC顯著地誘導GBM 8401細胞中G2/M期停滯和sub-G1期增加 (細胞凋亡族群)。以CDK1活性測定和西方墨點法分析發現AITC能明顯降低CDK1/cyclin B的活性和蛋白層次的影響。藉由形態的檢測及DAPI染色觀察證實AITC能誘導產生細胞凋亡。經預處理特異性caspase-3抑制劑 (Z-DEVE-FMK) 和caspase-9抑制劑 (Z-LEHD-FMK)可以顯著地降低GBM 8401細胞中casapse-3和-9的活性。由西方墨點法和比色法 (colorimetric assay)檢測也顯示AITC造成時間依賴性地增加細胞質內cytochrome c、pro-caspase-9、Apaf-1、AIF、Endo G蛋白層次且刺激caspase-9和-3活性。由我們的結果推測AITC是一種具有潛力能抗人腦惡性膠質瘤的藥物,且它可先誘導細胞週期停滯後造成細胞凋亡現象的產生。
第二部分:表沒食子兒茶素沒食子酸酯 (epigallocatechin-3-gallate; EGCG)是一種存在於綠茶中的多酚類成分,有研究指出在離體 (in vitro)和活體 (in vivo)實驗中可抑制癌細胞的生長。然而,在台灣特定的人類膀胱癌細胞試驗上是有限的且無良好的研究。因此,我們的研究著重於評估EGCG在台灣特定人類膀胱癌TSGH-8301細胞離體和活體中引發的細胞凋亡及其相關分子機制的探討。在活體研究中,EGCG在裸小鼠動物模式上可抑制異種移植 (xenograft) TSGH-8301腫瘤大小。在離體研究中,結果包括:EGCG影響TSGH-8301細胞形態上的改變和抑制其生長且有劑量和時間依存性。再者,在EGCG處理TSGH-8301細胞中可使sub-G1族群出現和活化caspase-9和-3活性。此外,使用caspase-9抑制劑 (Z-LEHD-FMK)和caspase-3抑制劑 (Z-DEVD-FMK) 分別能夠降低EGCG刺激的caspase-9和-3活性。TSGH-8301細胞在處理EGCG後導致粒線體膜電位 (mitochondrial membrane potential; ΔΨm)下降與促使cytochrome c、Apaf-1、caspase-9和-3蛋白質層次增加。由蛋白質體學分析發現EGCG在TSGH-8301細胞中影響多種蛋白質的表現,包括:熱休克蛋白27 (HSP27)、Porin、Tropomyosin 3 isoform 2、Prohibitin和keratin 5、14、17等。EGCG還能抑制AKT激酶活性和蛋白層次及改變Bcl-2家族相關的蛋白質層次的影響,如:Bcl-2、Bax、BAD和p-BAD。根據上述發現顯示,EGCG在TSGH-8301細胞中挑起的細胞凋亡主要藉由針對AKT和HSP27與調控p-BAD後,導致活化內在細胞凋亡連鎖路徑。

Recent studies have shown there is a strong link between diet and cancer. Moreover, these studies have shown that certain foods can lower the chances of getting cancer. In general, there are two active parts in these foods, namely pertaining to oil solubility or water solubility. The first part of this paper discusses how oil soluble Allyl isothiocyanate triggers G2/M phase arrest and apoptosis in human brain malignant glioma GBM 8401 cells, through a mitochondria-dependent pathway. The second part uses a proteomic approach to studying water soluble epigallocatechin gallate-provoked apoptosis of TSGH-8301 in human urinary bladder carcinoma cells: roles of AKT and heat shock protein 27-modulated intrinsic apoptotic pathways.
PART I. Isothiocyanates (ITCs) are present as glucosinolates in various cruciferous vegetables. Allyl isothiocyanate (AITC) is one the common naturally occurring isothiocyanates. Recent studies have shown that AITC significantly inhibited survival of leukemia HL-60, bladder cancer UM-UC-3 and colon cancer HT-29 cancer cells in vitro. In this study, we demonstrate that AITC significantly decreased proliferation and viability of human brain malignant glioma GBM 8401 cells in a dose-dependent manner with the half maximal inhibitory concentration (IC50) 9.25±0.69 μM for 24 h-treatment. The analysis of cell cycle distribution also showed that AITC induced significantly G2/M arrest and sub-G1 phase (apoptotic population) in GBM 8401 cells. AITC markedly reduced the CDK1/cyclin B activity and protein levels by CDK1 activity assay and Western blot analysis. AITC-induced apoptotic cell death and this evidence was confirmed by morphological assessment and DAPI staining. Pretreatment with specific inhibitors of caspase-3 (Z-DEVE-FMK) and -9 (Z-LEHD-FMK) significantly reduced the casapse-3 and -9 activities in GBM 8401 cells. Western blot analysis and colorimetric assays also displayed that AITC caused a time-dependent increase in cytosolic cytochrome c, pro-caspase-9, Apaf-1, AIF, Endo G and the stimulated caspase-9 and -3 activity. Our results suggest that AITC is a potent anti-human brain malignant glioma drug and it shows a remarkable action on cell cycle arrest before commitment for apoptosis is reached.
PART II. Epigallocatechin-3-gallate (EGCG), a polyphenol constituent presented in green tea, has shown to inhibit the growth of cancer cells in vitro and in vivo. However, the studies regarding Taiwan specific human bladder carcinoma cells are limited and not well investigated. Hence, our study focused on evaluation of EGCG-triggered apoptosis in Taiwan specific human urinary bladder carcinoma TSGH-8301 cells in vivo and in vitro as well as its related molecular mechanisms. In in-vivo study, EGCG inhibited xenograft tumor size of TSGH-8301 cells in a nude mouse model. In in-vitro study, the results included that EGCG affected morphological changes and increased a growth inhibitory in a dose- and time-dependent manner in TSGH-8301 cells. Furthermore, sub-G1 populations were shown and caspase-9 and -3 activities were stimulated in EGCG-treated TSGH-8301 cells. Moreover, a caspase-9 inhibitor (Z-LEHD-FMK) and a caspase-3 inhibitor (Z-DEVD-FMK) are able to reduce EGCG-stimulated caspase-9 and -3 activities, respectively. Loss of mitochondrial membrane potential (ΔΨm) resulted in the increases of protein levels in cytochrome c, Apaf-1, caspase-9 and -3 in TSGH-8301 cells after exposure to EGCG. Proteomic analysis discovered that EGCG affected the expression levels of various proteins, including HSP27, porin, tropomyosin 3 isoform 2, prohibitin and keratin 5, 14, 17 in TSGH-8301 cells. EGCG also suppressed AKT kinase activity and protein levels as well as altered Bcl-2 family-related protein levels such as Bcl-2, Bax, BAD and p-BAD. Based on the above findings, this study suggest that EGCG-provoked apoptotic death in TSGH-8301 cells is mediated through targeting the AKT and HSP27 and modulating the p-BAD, leading to activate the intrinsic apoptotic cascade pathway.
其他識別: U0005-2001201211142000
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