乳癌在台灣是婦女死亡原因的第四名，同時也是全世界女性癌症死亡的主因，流行病學及飲食習慣的研究指出大量攝取十字花科的蔬菜可以防止癌症的發生。Indole-3-carbinol (I3C) 是一個食物中的天然化合物，存在於芸苔屬植物中，例如：甘藍菜、花椰菜及球芽甘藍。 Indole-3-carbinol以及它的代謝產物：3,3’-diindolylmethane藉由調控許多與細胞週期(cell cycle)及細胞存活(cell survival)有關的訊息傳導路徑例如：Akt-NFκB signaling, caspase activation, cycle-dependent kinase activities, estrogen receptor signaling, endoplasmic reticulum stress and BRCA gene expression等來抑制癌症的發生與生長。I3C及DIM在過去的報導中已被發現具有抑制癌細胞生長及誘導細胞週期停止在G1 phase的功能，但是其有效濃度仍然偏高(I3C: 100~200 μM；DIM: 30~60 μM)，因此許多研究團隊正著力於合成更具效力的吲哚(Indole)衍生物。

本論文第一部份的研究，我們於一系列的吲哚衍生物中篩選出最具有抗癌活性的化合物。首先，我們採用MTT assay來測試衍生物於人類乳癌細胞的cytotoxicity(細胞毒性)，在這一系列的衍生物當中，我們發現SK228其抑制癌細胞生長的效果最佳，IC50 (The half maximal inhibitory concentration)在MDA-MB-231及MCF7細胞中分別約為0.45與0.88 μM。其次，對於細胞週期的分析上發現SK228會誘使細胞週期停止於G2/M phase。除此之外，SK228也會誘導一些與細胞凋亡(apoptosis)有關的蛋白質表現，例如：調升bak, caspase-3 activation, PARP cleavage；調降bal-2，同時SK228也會引發genomic DNA的降解(degradation)。因此，我們的實驗結果指出SK228是一個具有潛力的化學治療藥物(chemotherapeutic agent)。

於第二部份的研究當中，我們將研究的重點放在探討SK228的抗癌機制。依據文獻的記載，I3C及DIM能夠調升E-cadherin的表現並且抑制癌細胞的移動(migration)、侵犯(invasion)及轉移(metastasis)的能力。E-cadherin的不表現是EMT的重要指標，因此我們假設SK228也具有相同的活性來反轉表皮-間質細胞轉型(epithelial-mesenchymal transition, EMT)，我們的研究發現SK228能夠調升E-cadherin蛋白質及mRNA的表現量並且抑制乳癌細胞的移動(migration)及侵犯(invasion)的能力。除此之外，經由SK228處理後的乳癌細胞其外觀由fibroblastoid(纖維母細胞型態)轉變為cobblestone-like appearance(鵝卵石型態)。我們同時也分析了幾個EMT inducer，其中ZEB1、ZEB2、Slug以及Twist1的表現量會被SK228所調降。miRNA在近年來也被報導與EMT的調節有關，除此之外I3C與DIM亦被發現能夠調升miRNA-200 family來達到調控EMT的目的。在研究中，我們發現經由SK228處理過的乳癌細胞其miRNA-200 family，尤其是miR-200c會被大量提升並接著抑制ZEB1的表現。對於SK228如何調控miRNA-200c的表現，我們進行了表觀遺傳調控(epigenetic regulation)的分析，實驗結果發現在SK228處理過後的癌細胞中，其histone deacetylase (HDAC) 活性下降了約25%，而在miRNA-200c-targeting-specific promoter methylation的分析上，則只約有6%的抑制作用。總括而言，我們的研究證實了SK228能夠調升miRNA-200 family的表現，而抑制了ZEB1進而使得E-cadherin表現上升來達到抑制癌細胞轉移的目的。

Breast cancer is the leading cause of death among Taiwanese women as well as women all over the world. Epidemiological and dietary studies have shown that high dietary intake of cruciferous vegetables protect against carcinogenesis. The dietary compound, indole-3-carbinol (I3C), is an autolysis product of glucosinolate, glucobrassicin, which is found in Brassica vegetables such as cabbage, broccoli and brussels sprouts. Indole-3-carbinol and its metabolite 3,3’-diindolylmethane target multiple aspects of cancer cell-cycle regulation and survival including Akt-NFκB signaling, caspase activation, cycle-dependent kinase activities, estrogen receptor signaling, endoplasmic reticulum stress and BRCA gene expression. The development of new and efficient synthetic methods to prepare indole derivatives continues to receive a lot attention in organic synthesis because of their biological activities. Various indole moieties occur in many pharmacologically and biologically active compounds. For instance, the simplest indole derivative such as indole-3-carbinol is a potential inhibitor of the growth of breast cancer and can induce the arrest of the cell cycle in G1 phase. 3, 3’-Diindoylmethane that derived from indole-3-carbinol by acid treatment, is also reported to possess the same activity. Therefore, several research groups are devoted their research towards the synthesis of various indole derivatives.

In the part I, we examined a series of tetraindole related derivatives to explore their cellular cytotoxicity for further development of new chemotherapeutic agents. First, the cytotoxicity was evaluated by MTT assay. The results indicated that a tetraindole derivative named SK228 has the best IC50 value at about 0.45 μM and 0.88 μM in MDA-MB-231 and MCF7 cells respectively. Second, the cell cycle was arrested in G2/M phase by SK228 treatment. Third, the SK228 induces the up-regulation of apoptosis-related proteins, such as bak, activated caspase-3, and cleaved PARP, and the down-regulation of bcl-2. Finally, the degradation of genomic DNA was also induced by SK228 treatment. Taken together; our results suggested the tetraindole derivative, SK228, is a potent chemotherapeutic agent.

In the part II, as I3C can induce the expression of E-cadherin and repress the cancer cells motility in vivo, we hypothesized that SK228 can induce the reversion of epithelial-mesenchymal transition (EMT) via the similar signaling pathway. First, we found that the cell-cell adhesion glycoprotein, E-cadherin, was up-regulated in both RNA and protein levels after SK228 treatment. Second, the in vitro migration and invasion activities of breast cancer cells were repressed by SK228. Moreover, the cell morphology was changed from fibroblastoid to epithelial cobblestone-like appearance after incubated with SK228. Several EMT-inducing transcription factors and E-cadherin transcriptional repressors such as Twist1, ZEB1 (δEF1), ZEB2 (SIP1) and Slug (Snail2) were also down-regulated by SK228. Moreover, we also found SK228 can up-regulate the expression of miRNA-200 family (especially miR-200c) by possibly inhibiting HDAC (histone deacetylase) activities. Our study suggested that SK228 can regulate the miR-200/ZEB1/E-cadherin pathway to reverse the epithelial-mesenchymal transition. However, the detail mechanisms which involved in the regulation of miRNA by SK228 still need to be addressed.

摘要 xi
Abstract xiii
Part I Evaluate the effects of SK228 on cell proliferation, cell cycle regulation and induction of apoptosis in human breast cancer cells 1
Introduction 2
Materials and methods 4
1. Cell culture: 4
2. Cell viability analysis: 4
3. Trypan blue dye exclusion assay: 5
4. Flow cytometry analysis: 5
5. Apoptosis detection by annexin V-FITV/propidium iodide binding assay: 6
6. Determination of the apoptotic DNA ladder 6
7. Protein extraction and Western blot analysis: 6
Results and discussion 8
1. Growth inhibition of tetraindoles against human cancer cells. 8
2. SK228 induces G2/M phase arrest in human breast cancer cells. 9
3. SK228 induces apoptosis in human breast cancer cells. 10
Part II Investigate the effects of SK228 on migration, invasion and EMT regulation in human breast cancer cell lines 42
Introduction 43
Materials and methods 45
1. Cell culture: 45
2. Cell viability analysis: 45
3. Protein extraction and Western blot analysis: 46
4. RNA isolation: 47
5. Reverse transcription-PCR: 47
6. miRNA real-time reverse transcription-PCR: 48
7. Migration assay: 48
8. Invasion assay: 49
9. Immunofluorescence staining: 49
10. Transfection: 49
11. HDAC assay: 50
12. DNA methylation analysis: 50
13. miRNA microarray: 51
14. Statistics: 51
Results and discussions 52
1. SK228 reduces the in vitro migration and invasion activities of cancer cells. 52
2. SK228 treatment leads to the regulation of EMT marker expression and the reversal of EMT in human breast cancer cells. 54
3. Regulation of miRNA-200 family expression by SK228 in breast cancer cells. 57
4. SK228 inhibits histone deacetylase activities in breast cancer cells. 59
Conclusion 60
Reference List 90

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