臺灣博碩士論文加值系統

做為治療疾病藥物之來源，天然物扮演了非常重要的角色，其獨特的結構與活性，對於新藥的發現與發展都十分具有幫助。由於知識與技術上的原因，在過去發現許多的海洋天然物並未就其分子作用機制做深入的研究與探討
。在本研究中，我們將探討從海洋菌Zooshikella sp.中所萃取出的紅色色素是否具有抗癌活性。藉由測定經過不同濃度的萃取物處理之後的癌症細胞株之細胞活性與增殖能力，我們證實了由Zooshikella sp.中所萃取出的紅色萃取物，對於癌細胞的確具有細胞毒性。經過一系列的驗證與純化，我們最後得到兩個具有相似結構的化合物，分別為WYT1-70-6 (prodigiosin) 與WYT1-70-10 (2-methyl-3-hep
-tyl prodigiosin)。兩者在抑制細胞增殖與誘發細胞凋亡的能力表現相當接近，此現象可由多二磷酸腺苷核糖聚合酶(PARP)被切割的情況證明。然而，根據結果發現即使結構相近，prodigiosin可以抑制腫瘤壞死因子α (TNFα) 在多發性骨髓瘤(multiple myeloma) 所引發的NF-κB核轉移與活化；而2-methyl-3-heptyl prodigiosin則無此現象。最後，我們證實了prodigiosin可與bortezomib共同作用而得到更好的細胞毒殺性。總結來說，我們的實驗結果顯示：由於抑制了轉錄因子NF-κB的活性，由Zooshikella sp.所純化出的天然物prodigiosin展現了抗癌活性，並與bortezomib在細胞毒殺能力上具有加成性。

Natural products are important sources of bioactive agents for treating diseases. The unique structures and novel activities of marine natural products represent a promising field for drug discovery. For historical reasons, the molecular mechanisms of many bioactive marine natural products have not been well elucidated. In this study, we aimed to investigate the anticancer activity of natural products isolated from Zooshikella sp., a marine bacterial species producing red pigments. By assessing the viability and proliferation of cancer cell lines treated with various concentrations of purified extracts/compounds, we have identified several bioactive extracts/molecules from Zooshikella sp. with cell toxicity. Moreover, two of the pure compounds, prodigiosin (WYT1-70-6) and its analog 2-methyl-3-heptyl prodigiosin (WYT1-70-10), induced apoptosis in cancer cell lines, as judged by the site-specific cleavage of PARP. Additionally, our preliminary data have shown that prodigiosin, but not 2-methyl-3-heptyl prodigiosin, inhibited TNFα induced NF-κB nuclear translocation and activation in the RPMI 8226 multiple myeloma cell line. Finally, we demonstrated that prodigiosin in combination with bortezomib had synergistic cell toxicity. In summary, results from this study suggested that marine natural product prodigiosin isolated from Zooshikella sp. exerts anticancer activity and additive interaction with bortezomib by targeting the transcription factor NF-κB signaling pathway.

CONTENTS

Abstract (Chinese)……………………………….…………………………………….i
Abstract (English)………………………………………………………..……………ii
Acknowledgement .........................................................................................................iii
Contents………………………………………………………………………………iv
List of Figures……………………………………...………………………………...vii
Appendix…………………………………………...……………………………… .viii
List of Abbreviations………………………………………………………..………...ix

Chapter 1. Introduction
1.1. Natural products 1
1.1.1. The sources of natural products 1
1.1.2. The value of application in clinical 3
1.2. NF-κB signal transduction pathway 3
1.2.1. Components and function of NF-κB complex 5
1.2.2. The IκB family 6
1.2.3. The IκB kinase (IKK) complex 7
1.2.4. Activation of NF-κB signaling pathway 8
1.2.4.1. Tumor necrosis factor receptor (TNFR) 9
1.2.4.2. Toll/interleukin-1 receptor (TIR) 9
1.2.4.3. T-cell receptor and B-cell receptor (TCR and BCR) 10
1.3. Inflammation and cancer 10
1.3.1. NF-κB dysregulation and caner 11
1.4. Multiple myeloma 13
1.4.1. NF-κB and multiple myeloma 13
1.4.2. The treatment of multiple myeloma 14
Specific aims 16

Materials and Methods
2.1. Materials 17
2.1.1. Chemicals and reagents 17
2.1.2. Equipment and materials 20
2.1.3. Buffers 21
2.2. Cell culture 22
2.2.1. Cell lines 22
2.2.2. General culturing of cells 22
2.3 Cell viability assay 22
2.4. Cell treatment 23
2.4.1. NF-κB inhibition treatment 23
2.4.2. Cell apoptosis treatment 24
2.5. Preparation of whole cell lysates and nuclear extract 24
2.5.1. Preparation of whole cell lysates 24
2.5.2. Preparation of nuclear extracts 24
2.6. SDS-polyacrylamide gel electrophoresis 25
2.7. Western blot analysis 26
2.8. Electrophoretic mobility shift assay (EMSA) 27

Chapter 3. Results
3.1. Transcription factor NF-κB inhibitor screening from marine natural products 29
3.2. WYT1-33-6 inhibits NF-κB activation by blocking IκBα phosphorylation and NF-κB nuclear translocation in TNFα-induced NIH3T3 cells 29
3.3. WYT1-33-6 inhibits cell viability and induces apoptosis in the human cervical cancer HeLa cells 30
3.4. Major bioactive components of WYT1-33-6, WYT170-6 (prodigiosin) and WYT1-70-10 (a prodigiosin analog), are cytotoxins in multiple myeloma cells 32
3.5. The DNA binding ability of NF-κB is inhibited by WYT1-70-6 through blocking NF-κB translocation in human multiple myeloma RPMI 8226 cells 33
3.6. Evaluating the cell killing effect of WYT1-70-6 in combination with clinical agents for treating multiple myeloma 34

Chapter 4. Discussion
4.1. Marine microorganism Zooshikella sp., a new source of prodiginine family 36
4.2. Prodigiosin has gotten attention again as an anticancer agent in recent years 36
4.3. Prodigiosin inhibits NF-κB signaling pathway in cancer cells 37
4.4. Prodigiosin in combination with bortezomib exert synergistic cell toxicity in hu-man multiple myeloma cells 37

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