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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許麗卿(Lih-Ching Hsu) | |
| dc.contributor.author | Yi-Ning Deng | en |
| dc.contributor.author | 鄧依寧 | zh_TW |
| dc.date.accessioned | 2021-07-11T14:50:17Z | - |
| dc.date.available | 2025-08-07 | |
| dc.date.copyright | 2020-09-10 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-07 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78304 | - |
| dc.description.abstract | 乳癌是全世界女性中最常見的惡性腫瘤，其發生率或致死率都居高不下。雙氫青蒿素 (Dihydroartemisinin, DHA) 是青蒿素衍生物主要的活性代謝物，也是用於治療瘧疾的著名藥物。先前文獻研究，DHA對多種人類癌症具有抗腫瘤作用，但其化學不穩定性以及葡萄醣醛酸化作用可將其迅速消除，導致半衰期短。為了解決穩定性不好的問題，且增加對癌細胞的細胞毒性作用，合成了一系列的膽酸與雙氫青蒿素混成化合物 (bile acid-dihydroartemisinin, BA-DHA)。我們先前研究發現在膽酸與雙氫青蒿素混成化合物中，UDC-DHA、HDC-DHA 和N3UDC-DHA在HepG2及HL-60效用最好。在這篇研究，我們針對乳癌細胞株也可觀察到此結果。DHA對MCF-7 細胞的 IC50 值約為40μM; UDC-DHA、HDC-DHA 和N3UDC-DHA的 IC50 值約為2 μM，為DHA 20倍的功效。針對MDA-MB-231細胞，DHA的 IC50 值約為100 μM; HDC-DHA 和N3UDC-DHA的 IC50 值分別約為20 μM及40 μM，為DHA 2.5-5倍的功效。雙氫青蒿素混成化合物比 DHA和相對應膽酸以 1:1 莫爾比率的合併使用更有效。探討在MCF-7中，DHA、HDC-DHA 和N3UDC-DHA之作用機轉，並使用相等功效的濃度進行實驗。在培養液及細胞中，可以發現UDC-DHA、HDC-DHA 和N3UDC-DHA較 DHA穩定，而DHA相較HDC-DHA 和N3UDC-DHA更快展現細胞毒性。可以觀察到HDC-DHA及N3UDC-DHA引起細胞停滯於 G0/G1 期和增加代表細胞凋亡的 subG1 細胞群，並發現可降低cyclin D、cyclin B、cyclin E的表達及提高p21、p27的表達。DHA、HDC-DHA及N3UDC-DHA在MCF-7細胞中通過內在凋亡途徑在MCF-7細胞中發揮細胞毒性作用。DHA、HDC-DHA及N3UDC-DHA誘導粒線體活性含氧物 (reactive oxygen species, ROS)並誘發細胞質ROS，隨後導致粒線體膜電位去極化。結果更進一步顯示ROS 的誘發及粒線體膜電位去極化皆可被抗氧化劑 N-acetylcysteine (NAC) 抑制，因此說明此ROS促成 DHA、HDC-DHA及N3UDC-DHA的抗癌作用。在處理DHA、HDC-DHA及N3UDC-DHA後可以使Chk2 磷酸化及g-H2AX上升且增加 p53 表現及活化以及Rad51代表的HR修復途徑下降，顯示出DNA 破壞性。在處理DHA、HDC-DHA及N3UDC-DHA後，可提升AMPK/ autophagy途徑。此外，DHA、HDC-DHA及N3UDC-DHA可抑制細胞遷移。Akt/mTOR 訊息傳遞路徑與細胞生長有相關性，此路徑在一般抗癌情況會被抑制，意外地是，在加藥處理後DHA、HDC-DHA及N3UDC-DHA誘導該路徑。因此將Akt抑製劑MK-2206與膽DHA、HDC-DHA及N3UDC-DHA做合併，顯示出協同作用。綜合以上所述，HDC-DHA及N3UDC-DHA可做為對抗乳癌的候選藥物。 | zh_TW |
| dc.description.abstract | Breast cancer is the most common malignancy in women worldwide, in which incidence and the lethal rate remain high. Dihydroartemisinin (DHA) is the main active metabolite of artemisinin derivatives and also a well-known anti-malaria drug. Previous studies have shown that DHA has antitumor effects in a variety of human cancers, but it can be rapidly eliminated by glucuronidation and it is highly chemically fragile, resulting in a short half-life. To solve the problem of poor stability and increase the cytotoxic effect on cancer cells, a series of bile acid-dihydroartemisinin (BA-DHA) compounds were synthesized. Our previous studies have found that UDC-DHA, HDC-DHA and N3UDC-DHA are the most effective compounds in HepG2 and in HL-60 cells. In this study, we also observed anticancer activity against breast cancer cells. The IC50 value of DHA for MCF-7 cells was ~40 μM; and the IC50 value of HDC-DHA and N3UDC-DHA was ~2 μM, which was 20 times more potent than DHA. The IC50 value of DHA for MDA-MB-231 cells was 100 μM; and the IC50 values of HDC-DHA and N3UDC-DHA were 20 μM and 40 μM, respectively, which were 2.5-5 times more potent than DHA. The BA-DHA hybrids were more effective than the combination of DHA with the corresponding bile acid at a 1:1 molar ratio. The mechanism of action of DHA, HDC-DHA, and N3UDC-DHA was investigated using concentrations of equal efficacy in MCF-7 cells. In the medium and cells, UDC-DHA, HDC-DHA and N3UDC-DHA were more stable than DHA, while DHA showed cytotoxicity faster than HDC-DHA and N3UDC-DHA. HDC-DHA and N3UDC-DHA caused G0/G1 arrest and increased subG1 cell population that represents apoptosis., These compounds reduced the expression of cyclin D, cyclin B, cyclin E and increased the p21 and p27 levels. DHA, HDC-DHA and N3UDC-DHA exerted cytotoxicity in MCF-7 cells through the intrinsic apoptotic pathway. DHA, HDC-DHA and N3UDC-DHA induced mitochondrial reactive oxygen species (ROS) and subsequently cellular ROS, finally led to mitochondrial membrane potential loss. The induction of ROS and MMP loss was attenuated by an antioxidant N-acetylcysteine (NAC), suggesting that ROS contributed to the anticancer effects of DHA, HDC-DHA and N3UDC-DHA. After treatment with DHA, HDC-DHA and N3UDC-DHA, p-Chk2, g-H2AX and p53 were upregulated, and Rad51 involved in HR repair was downregulated, indicative of DNA damage response. The AMPK/autophagy pathway was also activated by DHA, HDC-DHA and N3UDC-DHA. Furthermore, DHA, HDC-DHA and N3UDC-DHA inhibited cell migration. The Akt/mTOR signaling pathway is related to cell growth. This pathway is usually inhibited in general anti-cancer treatment. Unexpectedly, DHA, HDC-DHA and N3UDC-DHA induced this pathway. Therefore, an Akt inhibitor MK-2206 was combined with DHA, HDC-DHA and N3UDC-DHA and displayed a synergistic effect. All in all, HDC-DHA and N3UDC-DHA can be used as drug candidates against breast cancer. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T14:50:17Z (GMT). No. of bitstreams: 1 U0001-0708202013361900.pdf: 7651998 bytes, checksum: ccd34c892481ebd393b44c417c92637f (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | Contents 誌謝 ii 中文摘要 iii Abstract v Contents vii List of Figures xii List of Tables xv List of Abbreviations xvi Aim of the study 1 Chapter 1. Introduction 2 1.1. Breast cancer 2 1.1.1 Incidence and mortality rates 2 1.1.2 Risk factors 2 1.1.3 Symptoms 3 1.1.4 Staging and the corresponding 5-year survival rates 3 1.1.5 Treatment 4 1.2. Human breast cancer cell lines 6 1.3. Dihydroartemisinin (DHA) 7 1.4. Bile acid-dihydroartemisinin (BA-DHA) hybrids 8 1.5. Cell cycle 9 1.6. Oxidative stress 10 1.7. Programmed cell death 11 1.7.1. Apoptosis 11 1.7.2. Autophagy 13 1.7.3. Necroptosis 14 1.8. DNA damage signaling and DNA double-strand breaks repairs 14 1.9. Epithelial-mesenchymal transition (EMT) 15 1.10. The MAPK pathways 16 1.11. The Akt/mTOR pathway 17 Chapter 2. Materials and Methods 24 2.1. Materials 24 2.2. Methods 25 2.2.1. Cell culture 25 2.2.2. Cell viability assay 25 2.2.3. Propidium iodide staining 26 2.2.4. Annexin V-FITC/PI double staining 27 2.2.5. DCFH-DA assay 27 2.2.6. MitoSOX assay 28 2.2.7. JC-1 assay 28 2.2.8. Wound healing assay 29 2.2.9. Western blotting 29 2.2.10. Data analysis 31 Chapter 3. Results 32 3.1. Effects of DHA and BA-DHA hybrids UDC-DHA, HDC-DHA and N3UDC-DHA on cell viability of MCF-7 and MDA-MB-231 cells 32 3.2. Comparing the cytotoxicity of BA-DHA hybrids to the combination of DHA with the respective BA. 33 3.3. Effects of an excess amount of bile acids on the growth inhibitory effect of HDC-DHA and N3UDC-DHA in MCF-7 cells. 33 3.4. Stability of DHA, UDC-DHA, HDC-DHA and N3UDC-DHA in the culture medium and in MCF-7 cells. 34 3.5. Effect of DHA, HDC-DHA and N3UDC-DHA on cell viability over time and clonogenicity of MCF-7 cells. 35 3.6. The impact of UGT inhibition on the growth inhibitory effect of DHA, HDC-DHA and N3UDC-DHA in MCF-7 cells. 36 3.7. Effects of DHA, HDC-DHA and N3UDC-DHA on cell cycle progression and apoptosis in MCF-7 cells 37 3.8. Effects of DHA, HDC-DHA and N3UDC-DHA on cellular and mitochondrial ROS production in MCF-7 cells 37 3.9. Effects of DHA, HDC-DHA and N3UDC-DHA on depolarization of MMP in MCF-7 cells 39 3.10. Effects of DHA, HDC-DHA and N3UDC-DHA on apoptosis induction in MCF-7 cells 40 3.11. Effects of DHA, HDC-DHA and N3UDC-DHA on DNA damage response in MCF-7 cells 41 3.12. Effects of DHA, HDC-DHA, and N3UDC-DHA on the AMPK/autophagy signaling pathways in MCF-7 cells 41 3.13. Inhibitory effects of DHA, HDC-DHA and N3UDC-DHA on MCF-7 cell migration. 42 3.14. Effects of DHA, HDC-DHA, and N3UDC-DHA on the MAPK signaling pathway in MCF-7 cells 43 3.15. Effects of DHA, HDC-DHA, and N3UDC-DHA on the Akt/mTOR signaling pathways in MCF-7 cells 44 3.16. An Akt inhibitor MK-2206 enhanced the anticancer activity of DHA, HDC-DHA, and N3UDC-DHA in MCF-7 cells and MDA-MB-231 cells 44 Chapter 4. Discussion 82 4.1. Anticancer activity of DHA, HDC-DHA and N3UDC-DHA against breast cancer cells. 82 4.2. BA-DHA hybrids is more potent than the combination of DHA with the respective BA in MCF-7 cells. 83 4.3. BA-DHA hybrids may not enter MCF-7 cells via bile acid transporters or receptors in MCF-7 cells. 83 4.4. UDC-DHA, HDC-DHA and N3UDC-DHA are more stable in the medium and cells. 84 4.5. Inhibition of UGT1A9 activity by 20 μM canagliflozin more effectively enhanced the anticancer effect of DHA than that of HDC-DHA and N3UDC-DHA in MCF-7 cells. 85 4.6. DHA, HDC-DHA, and N3UDC-DHA induced the cell cycle G0/G1 arrest in MCF-7 cells. 85 4.7. Induction of cellular and mitochondria ROS by DHA, HDC-DHA and N3UDC-DHA is correlated with drug stability. 86 4.8. MMP loss induced by DHA, HDC-DHA and N3UDC-DHA in MCF-7 cells is correlated with ROS. 87 4.9. DHA, HDC-DHA and N3UDC-DHA enhanced apoptosis via the intrinsic pathway in MCF-7 cells. 88 4.10. DHA, HDC-DHA and N3UDC-DHA activated DNA damage response and downregulated the HR repair system in MCF-7 cells. 89 4.11. DHA, HDC-DHA, and N3UDC-DHA upregulated AMPK mediated autophagy in MCF-7 cells. 89 4.12. DHA, HDC-DHA and N3UDC-DHA inhibited cell migration via downregulation of snail and upregulation of E-cadherin in MCF-7 cells. 90 4.13. DHA might hinder cell proliferation through the inactivation of the ERK signaling pathway 91 4.14. DHA, HDC-DHA and N3UDC-DHA may increase cellular stresses in MCF-7 cells, which led to Akt activation 91 4.15. The role of the Akt signaling pathway in DHA, HDC-DHA and N3UDC-DHA treatment 92 Chapter 5. Conclusion 93 References 96 | |
| dc.language.iso | zh-TW | |
| dc.subject | 膽酸與雙氫青蒿素混成化合物 | zh_TW |
| dc.subject | 乳癌 | zh_TW |
| dc.subject | DNA 損傷 | zh_TW |
| dc.subject | 粒線體膜電位去極化 | zh_TW |
| dc.subject | 氧化壓力 | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | 細胞自噬 | zh_TW |
| dc.subject | apoptosis | en |
| dc.subject | depolarization of MMP | en |
| dc.subject | DNA damage | en |
| dc.subject | breast cancer | en |
| dc.subject | bile acid-dihydroartemisinin hybrids | en |
| dc.subject | autophagy | en |
| dc.subject | oxidative stress | en |
| dc.title | 膽酸與雙氫青蒿素混成化合物於乳癌細胞株之抗癌活性評估 | zh_TW |
| dc.title | Evaluation of anticancer activity of bile acid-dihydroartemisinin hybrids in breast cancer cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 顧記華(Jih-Hwa Guh),孔繁璐(Fan-Lu Kung) | |
| dc.subject.keyword | 乳癌,膽酸與雙氫青蒿素混成化合物,細胞凋亡,氧化壓力,粒線體膜電位去極化,DNA 損傷,細胞自噬, | zh_TW |
| dc.subject.keyword | breast cancer,bile acid-dihydroartemisinin hybrids,apoptosis,oxidative stress,depolarization of MMP,DNA damage,autophagy, | en |
| dc.relation.page | 106 | |
| dc.identifier.doi | 10.6342/NTU202002623 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-08-10 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| dc.date.embargo-lift | 2025-08-07 | - |
| 顯示於系所單位： | 藥學系 | |
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