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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許麗卿(Lih-Ching Hsu) | |
| dc.contributor.author | Shao-Fu Wu | en |
| dc.contributor.author | 吳少夫 | zh_TW |
| dc.date.accessioned | 2021-06-16T06:36:07Z | - |
| dc.date.available | 2019-10-20 | |
| dc.date.copyright | 2014-10-20 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-08-01 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57146 | - |
| dc.description.abstract | BF65為全合成之hemiasterlin衍生物，並已知具有抗微管之作用。典型的hemiasterlins是萃取自海棉的天然化合物，具有三肽(tripeptide)結構，並可與α型微管結合，其結合位點鄰近於長春花生物鹼類(vinca-alkaloids)在β型微管的結合位點，能抑制微管的聚合。BF65除了可影響參與調控細胞週期蛋白質表現，並同時可引起細胞死亡的訊息傳遞，與長春花生物鹼類藥物如vincristine相似。我們利用人類急性前骨髓性細胞白血病(acute promyelocytic leukemia, APL)細胞株HL-60測試BF65的抗癌活性。APL屬於急性骨髓性細胞白血病(acute myelocytic leukemia, AML)下的第三亞型，目前臨床上的治療選擇包含許多化療藥物，如vincristine。已知的抗微管藥物大部分造成細胞週期停滯於有絲分裂階段(mitosis phase)，最終促使細胞凋亡(apoptosis)。然而我們發現HL-60受BF65處理過後也會造成磷酸化組織蛋白H2A.X(phospho-histone H2A.X, γ-H2AX)的蛋白質表現增加及進入S期的細胞數有微幅上升，前述均為DNA受損的表徵，且作用發生的時間點早於有絲分裂期的停滯與細胞凋亡。BF65除了造成γ-H2AX的增加之外，同時降低細胞內的轉錄訊息傳遞及活化子蛋白3(Stat3)與B細胞白血病淋巴瘤蛋白2(Bcl-2)的表現，BF65所引起的這些現象能受到c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)抑制劑SP600125所阻隔。此外我們也發現SP600125同時也能逆轉BF65所引發的粒線體膜電位喪失，但卻不影響細胞週期的改變。我們也注意到BF65能抑制細胞自噬作用(autophagy)。因此，我們推論BF65在抑制微管作用的同時，也會透過JNK的訊息傳遞途徑造成DNA損傷。而BF65抑制自噬和Stat3的能力可能有利於更進一步的抗癌應用。 | zh_TW |
| dc.description.abstract | BF65, a synthetic hemiasterlin, has been known for its anti-microtubule effect. Classic hemiasterlins are natural products extracted from marine sponges. With tripeptide-like structure, hemiasterlins bind to α-tubulin, but the binding site is close to the vinca alkaloid-binding site on β-tubulin, and inhibit tubulin polymerization. BF65 affects proteins involved in cell cycle regulation and signal transduction of cell death in a way similar to vinca alkaloids, such as vincristine. We test the anticancer activity of BF65 in HL-60, a human promyelocytic leukemia cell line. Acute promylocytic leukemia (APL) is a subtype (M3) of acute myeloid leukemia (AML) and several chemotherapy drugs have been approved for AML, including vincristine. Usual anti-microtubule agents cause cell cycle arrest in mitosis, eventually leading cells to apoptosis. However, we find that BF65 also induces increased level of phospho-histone H2A.X (γ-H2AX) and slightly elevates cell population at S-phase, both of which are markers for DNA damage, prior to M-phase arrest in HL-60. Interestingly, BF65-induced γ-H2AX can be partially reduced when c-Jun N-terminal kinase (JNK) is inhibited by SP600125. Moreover, BF65 downregulates signal transducer and activator of transcription 3 (Stat3) and B-cell leukemia lymphoma-2 (Bcl-2), which can be blocked by SP600125 without altering BF65-induced cell cycle arrest. Surprisingly, SP600125 is also able to reverse the mitochondrial membrane potential loss resulted from BF65 treatment. In addition, we notice that BF65 seems to inhibit autophagy. Thus, we propose that BF65 may also cause DNA damage through JNK-mediated pathway while inhibiting normal microtubule function. Besides, BF65-induced decrease in autophagic activity and Stat3 expression may be beneficial for further anticancer applications. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T06:36:07Z (GMT). No. of bitstreams: 1 ntu-103-R01423009-1.pdf: 2898193 bytes, checksum: 1eb20fa0bf670d5d765b8f9c95f95f30 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | Table of Contents
Certification by the Oral Defense Committee i Acknowledgements ii Chinese Abstract iii English Abstract iv Table of Contents vi List of Figures ix List of Tables xi List of Abbreviations xii I. Introduction 1 I-1 Acute promyelocytic leukemia and clinical therapy 1 I-2 Anti-microtubule agents 4 I-3 Hemiasterlins and BF65 5 I-4 DNA damage 6 I-5 Apoptosis 7 I-6 Autophagy 8 I-7 Role of Stat3 in leukemia 10 II. Research Significance and Objectives 20 III. Materials & Methods 21 III-1 Materials 21 III-2 Cell Line and Cell Culture 22 III-3 MTT Assay 22 III-4 SDS-PAGE and Western Blotting 22 III-5 Flow Cytometric Analysis of DNA Content 23 III-6 Flow cytometric assay of γ-H2AX and PI double staining 23 III-7 Immunofluorescence Staining 24 III-8 Comet Assay 25 III-9 Mitochondrial Membrane Potential Loss Detection 26 III-10 ROS Detecction 26 III-11 Statistical Analysis 27 IV. Results 28 IV-1 BF65 displays cytotoxicity in HL-60 28 IV-2 BF65 arrests the cell cycle at G2/M phase 28 IV-3 The effect of BF65 on cell cycle-related proteins 29 IV-4 The effect of BF65 on apoptosis-related signaling 30 IV-5 BF65 inhibits the formation of lipid-bounded LC3-II, a marker for autophagy 31 IV-6 BF65 induces the accumulation of γ-H2AX, a marker for DNA damage 32 IV-7 BF65 induces DNA damage and causes comet tails in the comet assay 33 IV-8 BF65 downregulates the expression of Stat3 33 IV-9 JNK inhibitor SP600125 can partially reverse BF65-induced DNA damage 34 IV-10 BF65 causes mitochondrial membrane potential (MMP) loss, which could be reversed by SP600125 35 IV-11 BF65 induces slight reactive oxygen species (ROS) generation, which could be blocked by SP600125 36 V. Discussion 37 V-1 BF65 displays cytotoxicity in HL-60 resulting in cell cycle arrest and apoptosis 37 V-2 Different from some anti-microtubule agents, BF65 inhibits autophagy rather than promotes autophagic activity in HL-60 37 V-3 BF65 may target mitochondria through JNK activation and Stat3 downregulation, eventually leading to DNA damage 38 V-4 The role of ROS in the anti-cancer mechanism of BF65 39 V-5 Potential of BF65 application in anti-leukemia therapy 39 VI. Conclusion 41 References 59 | |
| dc.language.iso | en | |
| dc.subject | BF65 | zh_TW |
| dc.subject | 抗微管 | zh_TW |
| dc.subject | DNA 損傷 | zh_TW |
| dc.subject | JNK | zh_TW |
| dc.subject | 細胞自噬 | zh_TW |
| dc.subject | 血癌 | zh_TW |
| dc.subject | hemiasterlins | zh_TW |
| dc.subject | anti-microtubule | en |
| dc.subject | JNK | en |
| dc.subject | autophagy | en |
| dc.subject | DNA damage | en |
| dc.subject | leukemia | en |
| dc.subject | hemiasterlins | en |
| dc.subject | BF65 | en |
| dc.title | Hemiasterlin衍生物BF65在血癌的抗癌機轉探討 | zh_TW |
| dc.title | Investigation of Anticancer Mechanisms of a Hemiasterlin Derivative BF65 in Leukemia Cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 孔繁璐,顧記華 | |
| dc.subject.keyword | BF65,hemiasterlins,抗微管,DNA 損傷,細胞自噬,JNK,血癌, | zh_TW |
| dc.subject.keyword | BF65,hemiasterlins,anti-microtubule,DNA damage,autophagy,JNK,leukemia, | en |
| dc.relation.page | 69 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-08-01 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| 顯示於系所單位： | 藥學系 | |
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