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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78971完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許麗卿 | zh_TW |
| dc.contributor.advisor | Lih-Ching Hsu | en |
| dc.contributor.author | 洪學致 | zh_TW |
| dc.contributor.author | Hsueh Chih Hung | en |
| dc.date.accessioned | 2021-07-11T15:33:15Z | - |
| dc.date.available | 2024-02-28 | - |
| dc.date.copyright | 2018-10-09 | - |
| dc.date.issued | 2018 | - |
| dc.date.submitted | 2002-01-01 | - |
| dc.identifier.citation | References
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78971 | - |
| dc.description.abstract | zh_TW | |
| dc.description.abstract | Tumor cells rely on aerobic glycolysis to support their anabolic growth and survival. GLUT1, one of the facilitative membrane transporters mediating glucose transport, is overexpressed in various cancers. Targeting GLUT1 has been considered as an emerging strategy to inhibit cancer cell proliferation. In this study, we first used a comprehensive virtual high-throughput screening (vHTS) protocol to search the NCI chemical library (NCI Diversity Set) for potential GLUT1 inhibitors. Seventy-five hits were further verified for inhibition of glucose uptake by a non-radioactive cell-based method using a fluorescent glucose analogue 2-NBDG as a substrate. This assay provided a rapid and direct glucose uptake measurement to determine the activity of GLUT inhibitors. The results showed that four of the 75 compounds had the inhibitory effect on GLUT1 and may serve as lead compounds for subsequent optimization.
In the present study, we use a well-known GLUT1 inhibitor, WZB117 and a potential hit #12 selected from the NCI Diversity Set to further evaluate the potential use of GLUT1 inhibitors in combinatorial cancer therapy. We found that the combination of WZB117 or #12 with metformin showed a synergistic growth inhibitory effect in ovarian cancer cells. The underlying mechanism was also investigated. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:33:15Z (GMT). No. of bitstreams: 1 ntu-107-R05423018-1.pdf: 2150018 bytes, checksum: 5ada6d1ce7b85c4f2f5027b16b9907a2 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
致謝 ii List of Abbreviations iii 中文摘要 iv Abstract v Contents vi Specific aims of the study 1 Chapter 1 Introduction 2 1.1 Glucose transporters 2 1.2 Cancer metabolism 3 1.3 Glucose uptake assay 4 1.4 Ovarian cancer 6 1.5 Ovarian cancer cell lines 9 1.6 Metformin 10 1.7 The PI3K/Akt/mTOR pathway 10 1.8 Programmed cell death 11 1.9 The MAPK pathway 12 1.10 Cancer metastasis 13 Chapter 2 Materials and Methods 14 2.1 Materials 14 2.2 Methods 15 2.2.1 Cell culture 15 2.2.2 2-NBDG uptake assay 15 2.2.3 2-NBDG flow cytometry analysis 15 2.2.4 Reverse transcriptase-polymerase chain reaction (RT-PCR) 16 2.2.5 Glucose Uptake-Glo™ Assay 17 2.2.6 Cell viability assay and combination index analysis 17 2.2.7 Colony formation assay 17 2.2.8 Cell cycle analysis with propidium iodide (PI) staining 18 2.2.9 Annexin V-FITC/PI double staining 18 2.2.10 Western blotting 18 2.2.11 Wound healing migration assay 20 2.2.12 Data analysis 20 Chapter 3 Results 21 3.1 Screening of potential GLUT inhibitors from the NCI Plated Set and NCI Diversity Set by 2-NBDG uptake assay 21 3.2 Validation of the potential GLUT inhibitors by Glucose Uptake-Glo™ Assay in COS-7 cells 22 3.3 Effects of the potential GLUT inhibitors on cell growth in SKOV3 cells 23 3.4 WZB117 and #12 when combined with metformin displayed a synergistic growth inhibitory effect in SKOV3 cells 23 3.5 Effects of combination of WZB117 and #12 with metformin on cell cycle progression in SKOV3 cells 24 3.6 Combination of #12 and metformin induces apoptosis in SKOV3 cells 24 3.7 Effects of WZB117, #12 and metformin on Akt/mTOR and MAPK signaling in SKOV3 cells 25 3.8 Effects of #12 and metformin on cell migration in SKOV3 cells 25 3.9 Effects of combination of WZB117 or #12 with metformin on cell growth of ES2 cells 26 Chapter 4 Discussion 44 4.1 Validation of a non-radioactive cell-based method for the screening of GLUT inhibitors 44 4.2 Screening and identification of potential GLUT inhibitors 45 4.3 GLUT inhibitors and metformin displayed synergistic growth inhibitory effect in SKOV3 cells 45 4.4 Effects of combination of WZB117 or #12 with metformin on cell cycle progression in SKOV3 cells 46 4.5 Combination of metformin and #12 induces apoptosis in SKOV3 cells 47 4.6 Effects of the WZB117/metformin and #12/metformin combinations on Akt/mTOR and MAPK signaling in SKOV3 cells 47 Chapter 5 Conclusion 52 Appendixes 53 References 58 | - |
| dc.language.iso | zh_TW | - |
| dc.title | 發展以第一型葡萄糖轉運蛋白為標的的新型抗癌藥物 | zh_TW |
| dc.title | Targeting GLUT1 for the development of novel anticancer agents | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 106-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 林榮信;顧記華 | zh_TW |
| dc.contributor.oralexamcommittee | ;; | en |
| dc.subject.keyword | GLUT1抑制劑,卵巢癌,metformin,WZB117, | zh_TW |
| dc.subject.keyword | GLUT1 inhibitors,ovarian cancer,metformin,WZB117, | en |
| dc.relation.page | 67 | - |
| dc.identifier.doi | 10.6342/NTU201803228 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2018-08-16 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 藥學研究所 | - |
| dc.date.embargo-lift | 2023-10-09 | - |
| 顯示於系所單位： | 藥學系 | |
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