臺灣博碩士論文加值系統

氟喹諾酮類抗生素是一種廣效型抗生素可用於治療各種細菌感染﹐近年來許多研究指出氟喹諾酮類抗生素除了具有抗菌功能之外還可以抗癌。已知氟喹諾酮類抗生素具有促進細胞凋亡、抑制癌細胞增生與加強化學療法等抗癌功能﹐然而其抗癌機制仍是未知﹐本論文將研究並探討氟喹諾酮類抗生素的抗癌機制。本篇研究發現在細胞實驗與小鼠模型當中﹐氟喹諾酮類抗生素可促進類胰島素生長因子結合蛋白3的生合成﹐研究指出氟喹諾酮類抗生素通過p53蛋白路徑以調控類胰島素生長因子結合蛋白3的生合成﹐由氟喹諾酮類抗生素誘導而產生之類胰島素生長因子結合蛋白3則會進一步抑制類胰島素生長因子下游訊息以及由類胰島素生長因子誘導之細胞增生。在同源腫瘤異體移植小鼠模型當中﹐研究發現環丙沙星可促進移植之肝癌細胞凋亡以此效抑制腫瘤生長﹐同時在肝癌腫瘤切片當中也觀察到類胰島素生長因子結合蛋白3表現量有所增加。本研究發現氟喹諾酮類抗生素透過調控類胰島素生長因子結合蛋白3表現的抗癌新機轉﹐未來將進一步探討關於氟喹諾酮類抗生素的抗癌用途與氟喹諾酮類衍生物的抗癌機轉﹐以此釐清氟喹諾酮類抗生是否可用於癌症治療。

Fluoroquinolones (FQs) are broad-spectrum antibiotics which are used to treat various bacterial infections. Apart from their antibacterial properties, evidence has implied their potential as an anticancer agent, with multiple anticancer activities including pro-apoptosis, antiproliferative, and enhancing chemotherapies. However, the mechanism underlying the anticancer activities of FQs remains unclear. Here, we found that the antiproliferative of FQs was mediated by inducing insulin-like growth factor binding protein-3 (IGFBP3) through a p53-dependent pathway. FQs-induced IGFBP3 suppressed IGF-I signaling and IGF-I-induced cell proliferation. Moreover, ciprofloxacin, a commonly used FQ, was found to attenuate growth of tumor in a syngeneic mouse tumor model of hepatocellular carcinoma by triggering apoptosis of tumor cells with upregulation of IGFBP3. Our results reveal a novel mechanism by which FQs exert their antiproliferative effect, prompting further investigation for their potential application and derivative compounds in treatment against cancer.

論文審定書 i
中文摘要 iii
Abstract iv
Table of Content v
Figure Index vii
Table of Appendix ix
Abbreviations x
1. Introduction 1
1.1 Fluoroquinolones 1
1.2 Classification of fluoroquinolones 2
1.3 Mechanism of action of FQs as antibacterial agents 3
1.4 The anticancer effects of FQs 4
1.4.1 FQs induce cell cycle arrest and inhibit cell proliferation 5
1.4.2 Proapoptotic effect of FQs 6
1.4.3 Modulation of epithelial-mesenchymal transition (EMT) and cell mobility in cancer cells 8
1.4.4 Improve the outcome of chemotherapy 9
1.5 IGFBP3 10
2. Methods and Materials 26
2.1. Cell culture and reagents 26
2.2. Animal experiments 26
2.3. Establishment of HCC in syngeneic mouse model 27
2.4. Hematoxylin & eosin staining and immunohistochemistry staining 28
2.5. TUNEL assay 29
2.6. MTT assay 30
2.7. BrdU assay 30
2.8. EdU cell proliferation assay 30
2.9. Preparation of conditional medium (CM) 31
2.10. Western blotting 31
2.11. Gene knockdown by siRNA transfection 32
2.12. Lentivirus-mediated shRNA knockdown 33
2.13. RNA extraction and RT-PCR 34
2.14. Quantitative-PCR 34
2.15. ELISA assay 35
2.16. Statistical analysis 36
3. Results 37
3.1 The effect of FQs on cell proliferation 37
3.2 FQs induced IGFBP3 expression 37
3.3 Ciprofloxacin induced IGFBP3 expression in mice model 39
3.4 Ciprofloxacin attenuated growth of tumor in the syngeneic mouse HCC model 40
3.5 FQs suppressed IGF-I signaling in HCC and mouse mammary gland epithelial cells and attenuated IGF-I-induced cell growth 41
3.6 FQs inhibited cell growth through inducing IGFBP3 expression 43
3.7 p53 was the key component for FQs to induce IGFBP3 expression 44
3.8 The antiproliferative effect of FQs mediated by IGFBP3 was p53-dependent 45
4. Discussions 80
5. References 89
6. Appendix 100
6.1 Supplemental Figures 100
6.2 Supplemental Materials 105
Publications 108

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