系統識別號 U0026-0808201313271800
論文名稱(中文) 植物鹼 CIL-102 抗神經癌活性之研究
論文名稱(英文) Studies of CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone) antitumor mechanisms and effects on gliomas
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 2
出版年 102
研究生(中文) 鄧志娟
研究生(英文) Chih-Chuan Teng
學號 S58951332
學位類別 博士
語文別 英文
論文頁數 97頁
口試委員 召集委員-簡伯武
中文關鍵字 神經膠質瘤  植物化學物質  細胞週期  凋亡  轉移 
英文關鍵字 GBM  CIL-102  cell cycle  apoptosis  meastasis 
中文摘要 神經膠質瘤(GBM),是種常見的惡性腫瘤,具有快速生長、易侵犯周邊組織的特性,因此在治療上較為困難,且復發率高。儘管醫學界一直積極的在尋找有效的治療方法,但是一直都遇到困難。在現今的癌症研究上,一些替代醫學(alternative medicine)提供了一些新的醫療選擇。就日前而言,化學預防(Chemoprevention);利用自然的食物成分或合成的化學因子,例如植物化學物質(phytochemicals),提供了有效的預防策略,針對抑制、延緩或回覆人類的癌化過程(carcinogenesis)。在這些植物化學物質中,多酚類(polyphenols)是一個大宗。不管在體外或體內的實驗中,均證明這些多酚類能有效的抵抗各種不同種類的癌症。CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone),來自於Camptotheca acuminata樹皮或莖(一種原生於中國的樹木)的一種生物鹼camptothecin之合成衍生物。針對特定的癌症而言,已知具有一些藥理功效,包括抗癌(anticancer)和促進細胞凋亡(apoptosis)。我們的實驗主要是針對神經膠質瘤的多樣性,希望提供植物鹼 CIL-102 抗神經癌活性之研究。在第一部分實驗中,我們發現CIL-102會因為影響reactive oxygen species (ROS)的生成;增加ROS的量,進而造成extracellular signal-related kinase (ERK1/2)磷酸化,降低細胞周期(cell cycle)相關蛋白表現 (cyclin A, cyclin B, cyclin D1, and cdk1),和磷酸化cdk1Tyr15 、 Cdc25cSer216,導致神經膠質瘤細胞的細胞周期停滯在G2/M期,最後引起神經膠質瘤細胞的死亡。接著,在第二部分,我們同時間發現,CIL-102會影響神經膠質瘤細胞的轉移能力(invasive)。透過蛋白質體學(proteomic approach)方法,我們找到更多CIL-102處理後,神經膠質瘤細胞上出現許多不同蛋白的表現。從實驗中發現,由於ROS的增加表現、引起JNK1/2 and p70S6K磷酸化,最後引起FUMH (Fumarate hydratase)增加表現,造成細胞的凋亡和抑制其轉移能力。從兩部分實驗中證明,CIL-102對神經膠質瘤細胞來說,一方面可以抑制癌細胞增生,另一方面又可抑制癌細胞的轉移。因此在治療神經膠質上應該是有一些程度的療效,能提供在未來神經膠質瘤的治療上,另一種選擇。最後,在第二部分實驗中,我們亦見到神經膠質瘤細胞在CIL-102處理後,還有許多不同的蛋白質表現差異,如Translationally-controlled tumor protein (TCTP)、Stathmin (STMN1)、Hypoxia up-regulated protein 1 (HYOU1) 和 Nucleophosmin (NPM)等,值得我們接下來對CIL-102的抗癌活性做更進一步的探討。
英文摘要 Low-grade diffuse gliomas WHO grade II (diffuse astrocytoma, oligoastrocytoma, oligodendroglioma), one of the most common malignant tumors, fast-growing, invasive, difficult to treat, and are likely to recur in worldwide. Despite intense efforts to develop treatments, effective agents are still not available. Complementary and alternative medicine tempts many efforts for new drug discovery in current cancer research. Chemoprevention is an active cancer preventive strategy to inhibit, delay or reverse human carcinogenesis, using naturally extracting or synthetic chemical agents, such as various phytochemicals. Among these phytochemicals, polyphenols are the largest in quantity among the phytochemicals. Several hundred scientific studies in the vitro or in the vivo all suggest a protective role of these dietary polyphenols against different types of cancer. CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone) is the major active agent of the alkaloid derivative of Camptotheca acuminata with multiple pharmacological activities, including anticancer effects and promotion of apoptosis.
The aims of research are to study the mechanism of CIL-102 affections on GBM cell lines. In our data, first, we found that the molecular mechanisms by which CIL-102 affects the generation of reactive oxygen species (ROS) and cell cycle G2/M arrest in glioma cells. Treatment of U87 cells with 1.0 µM CIL-102 resulted in phosphorylation of extracellular signal-related kinase (ERK1/2), downregulation of cell cycle-related proteins (cyclin A, cyclin B, cyclin D1, and cdk1), and phosphorylation of cdk1Tyr15 and Cdc25cSer216. Second, our results demonstrate that CIL-102 treatment of U87 cells results in decreased cell proliferation and invasiveness. Sustain phosphorylation of JNK1/2 and p70S6K, generation of the reactive oxygen species as well as up-regulating the levels of FUMH (Fumarate hydratase) inducing CIL-102 dose-dependent induction of apoptosis and inhibitory invasiveness. At last, by Proteomic approaches showed the significant differences in protein expression profiles in U87 cells upon CIL-102 treatments. It needs to be further study other differential proteins whether mediated actions in CIL-102 cultured cells.
The inhibitory effect of CIL-102 on the growth of human astrocytoma cells is mediated by the generation of reactive oxygen species and induction of ERK1/2 MAPK
2.2.1. Chemical reagents and antibodies 23
2.2.2. Cell culture 23
2.2.3. Cell growth and proliferation assay 24
2.2.4. Apoptosis assay and cell cycle distribution analysis 24
2.2.5. Preparation of total cell extracts and immunoblot analyses 25
2.2.6. Measurement of ROS 25
2.2.7. Statistical analysis 26
2.3. RESULT 27
2.3.1. Effects of CIL-102 on the viability of human astrocytoma cells 27
2.3.2. CIL-102 induces G2/M arrest in U87 cells 27
2.3.3. Involvement of ROS generation in CIL-102-inhibited cell proliferation 28
2.3.4. ROS and the Ras/ERK1/2 triggering pathway are involved in the regulation of CIL-102-induced G2/M arrest in U87 cells 28
2.3.5. Activation of ERK1/2 signaling pathway by CIL-102 in U87 cells 29
2.3.6. Effects of CIL-102 on the expression of Cdc25cSer216 and cell cycle related proteins in U87 cells 29
2.3.7. Regulation of the expression of cyclin A and cyclin B by ERK1/2 and Cdc25c 30
Quantitative proteomic analysis to the inhibitory effects of CIL-102 viability and invasiveness in human glioma cells
3.2.1. Cell culture 45
3.2.2. Chemical Reagents and Antibodies 45
3.2.3. Assessment of cell viability and apoptosis assay 46
3.2.4. Scratch assays 47
3.2.5. Boyden chamber assay 47
3.2.6. Second dimensional protein electrophoresis analysis of U87 cells proteomic profiles 48
3.2.7. In-gel digestion and identification of peptide fingerprints of with or without CIL-102 treatment using MALDI-TOF 49
3.2.8. Preparation of total cell extracts and immunoblot analyses 50
3.2.9. shRNA Lentivirus transfection 50
3.2.10. Measurement of reactive oxygen species 50
3.2.11. Statistical Analysis 51
3.3. RESULT 52
3.3.1. Anti-cancer activity of CIL-102 upon human astrocytoma cells 52
3.3.2. Proteomic profiling of U87 glioma cells treated with CIL-102 53
3.3.3. Validation of the differential proteins 2D results by western blotting 54
3.3.4. Functional validation of CIL-102 induced JNK 1/2 and mTOR signaling pathways as well as reactive oxygen species on apoptosis and invasion by knockdown of FUMH with short hairpin RNA (shRNA) in U87 cells 55
3.3.5. ROS generation and FUMH are involved in the regulation of the caspases and HIF1, MMP2 and MT1-MMP levels by CIL-102 in U87 cells 56
Drugs with similar antitumor mechanism to CIL-102, and potential usefulness of CIL-102 as an alternative for cancer therapy

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