臺灣博碩士論文加值系統

血液惡性疾病可以分為骨髓球性或淋巴球性，目前對於淋巴球性血液惡性疾病的標準治療方式為化學藥物治療加上單株抗體。雖然有部份淋巴球性惡性腫瘤的患者，例如瀰漫性大B細胞淋巴瘤，對於初始治療的效果不錯，但仍然有部份病人會因為腫瘤對化學藥物產生抗藥性而死亡，甚至有些病人在初始治療時就沒有效果。對於這些病人而言，其預後也非常不好，因此，如何增加淋巴球性惡性腫瘤的治療效果是一個重要課題。要克服此問題的一種方法是，研發具有與化學藥品不同作用機轉的藥物（另類路徑）來對抗癌細胞；另一個策略則是以此類藥物來增加癌細胞對化學藥物或其他藥品的敏感性。因此，我們假設作用在另類路徑的藥物本身就有抗淋巴球性腫瘤的效果，或者可以經由增加癌細胞對其他細胞毒殺藥物的敏感性來提高療效。在這裡，我們將由三個方向來驗證我們的假說。

實驗的第一部份證實OSU-DY7可以經由活化p38路徑而產生對慢性淋巴球性白血病或Burkitt淋巴瘤的療效。第二個部份證實一個組蛋白去乙醯酶的抑制劑(S)-HDAC42對多發性骨髓瘤的效果。最後我們用一個Akt路徑抑制劑OSU-03012增強imatinib對骨髓瘤細胞的毒殺作用，而此交互作用可能和AMP-活化蛋白激酶與STAT3路徑有關。因此我們的實驗證實，作用於p38 MAPK，Akt路徑或histone deacetylase的藥物可以用來治療淋巴球性血液惡性疾病。當然這方面的研究未來還需要更多實驗來檢視。

Hematological malignancies can be grouped as either myeloid or lymphoid disorders. The standard treatment strategy for lymphoid malignancies is chemotherapeutic agents, usually in combination with monoclonal antibodies which have introduced great impact on the clinical situation. Although certain subtypes of lymphoid malignancies, e.g. diffuse large B cell lymphoma, have good response to initial treatment, some of patients will succumb to the disease because of development of drug resistance. Still others are primarily refractory to initial therapy. The prognosis for these patients is dismal. This highlights the necessity of developing approaches to improve the therapeutic efficacy for lymphoid malignancies. One approach is to develop compounds that have anti-tumor effects with mechanism different from conventional chemotherapeutic agents. Another strategy to improve the therapeutic efficacy is to sensitize cancer cells to cytotoxic effect of other agents. We hypothesize that agents targeting alternative pathways are effective in treatment of lymphoid malignancies. These agents can exhibit anti-tumor efficacy either by themselves or by sensitizing cancer cells to other cytotoxic agents. For this sack, we validate our hypothesis through three approaches.

The first part demonstrates that OSU-DY7 induces cytotoxicity in chronic lymphocytic leukemia and Burkitt lymphoma through activating p38 mitogen-activated protein kinase pathway. The second part illustrates the effectiveness of a histone deacetylase inhibitor (S)-HDAC42 in multiple myeloma cells U266. The last part shows that OSU-03012, an Akt pathway inhibitor, sensitizes myeloma cells to imatinib mesylate via AMP-activated protein kinase and STAT3 pathways. Our study successfully proves the hypothesis that agents targeting p38 MAPK, Akt pathways or histone deacetylase are effective in treatment of lymphoid malignancies. Further studies are needed to shed more light on the road.

目 錄

中文摘要 (Abstract in Chinese) i
英文摘要 (Abstract in English) ii
致謝辭 (Acknowledgements) iv
目錄 (Table of contents) v
表目錄 (List of tables) viii
圖目錄 (List of figures) ix

第一章 研究動機與目的 (Chapter 1. Research Motivation and
Purpose) 1
1.1. Lymphoid malignancies 1
1.2. Treatment of lymphoid malignancies 1
1.3. Strategies to improve the therapeutic efficacy 2
1.4. Research hypothesis 2
1.5. Objective and approach 3

第二章 文獻回顧 (Chapter 2. Literature Review) 4
2.1. Chronic lymphocytic leukemia and Burkitt’s
lymphoma 4
2.2. Multiple myeloma 6
2.3. The difficulties we are facing with in managing patients with lymphoid malignancies 7
2.4. p38 MAPK 8
2.5. OSU-DY7 8
2.6. (S)-HDAC42 10
2.7. OSU-03012 11

第三章 測試p38 MAPK激活劑 OSU-DY7對淋巴球性白血病
及淋巴瘤的活性 (Testing the efficacy of a p38 MAPK activator OSU-DY7 in lymphocytic leukemia and lymphoma) 12
3.1. Introduction 12
3.2. Materials and Methods 13
3.3. Results 18
3.4. Discussion 26

第四章 以組織球蛋白去乙醯酶抑制劑 (S)-HDAC42來處理
多發性骨髓瘤細胞 (Chapter 4. Treating multiple myeloma with a novel histone deacetylase inhibitor (S)-HDAC42) 30
4.1. Introduction 30
4.2. Materials and Methods 30
4.3. Results 34
4.4. Discussion 36

第五章 以Akt路徑抑制劑OSU-03012來加強骨髓瘤細胞對
imatinib的敏感性 (Chapter 5. Improving the therapeutic efficacy by sensitizing myeloma cells to imatinib by an
Akt pathway inhibitor OSU-03012) 39
5.1. Introduction 39
5.2. Materials and Methods 40
5.3. Results 43
5.4. Discussion 45

第六章 結論與未來 (Chapter 6. Conclusion and prospective) 49

參考文獻 (References) 83


表目錄 (List of tables)
Table 1 IC50 values of OSU-DY7 in malignant lymphoid cell lines and primary B-CLL cells 51



圖目錄 (List of figures)

Figure 1 Compounds targeting alternative pathways other then chemotherapeutic agents maybe beneficial for lymphoid malignancies 52
Figure 2 The chemical structure of OSU-DY7 53
Figure 3 The chemical structures of (S)-HDAC42 and
suberoylanilide hydroxamic acid (SAHA) 54
Figure 4 The chemical structures of OSU-03012 55
Figure 5 The experiment flow chart of part I study (Testing the efficacy of a p38 MAPK activator OSU-DY7 in lymphocytic leukemia and lymphoma) 56
Figure 6 Cytotoxicity study of OSU-DY7 in B-lymphocytic cell lines and primary B CLL cells 57
Figure 7 OSU-DY7 induces cell morphological change in a
dose-dependent manner 58
Figure 8 OSU-DY7-mediated cytotoxicity is dependent on caspase activation and apoptosis 59
Figure 9 The effect of OSU-DY7 in pro- and anti-apoptotic protein expression in Raji and MEC-1 61
Figure 10 OSU-DY7 induces down regulation of phosphorylated
ERK1/2 and up regulation of phosphorylated p38 MAPK 62
Figure 11 OSU-DY7 induces phosphorylation of p38 MAPK 63
Figure 12 OSU-DY7-induced cytotoxicity is dependent on p38
MAPK activation 65
Figure 13 OSU-DY7-induced down regulation of BIRC5 protein
and mRNA transcription in p38 MAPK activation
dependent manner 67
Figure 14 Inhibition of ERK pathway has no effect on Raji cell survival 69
Figure 15 Quantitative polymerase chain reaction of cytokines in Raji cells treated with OSU-DY7 70
Figure 16 The proposed mechanism of OSU-DY7 mediated
cytotoxicity in CLL and Burkitt’s lymphoma 71
Figure 17 The experiment flow chart of part II study (Treating multiple myeloma U266 with a novel histone deacetylase inhibitor (S)-HDAC42) 72
Figure 18 Effects of (S)-HDAC42 on HDAC inhibition 73
Figure 19 Apoptotic assay of U266 cells treated with (S)-HDAC42 for 48 h 74
Figure 20 Western blot analysis of apoptotic pathway in U266 cells treated with (S)-HDAC42 for 48 h 75
Figure 21 Western blot analysis of Akt and NF-?羠 pathways and cell cycle related proteins in U266 cells treated with
(S)-HDAC42 for 48 h 76
Figure 22 The experiment flow chart of part III study (Improving the therapeutic efficacy by sensitizing myeloma cells to imatinib by an Akt pathway inhibitor OSU-03012) 78
Figure 23 OSU-03012 accentuates the cytotoxicity of imatinib
mesylate in U255 myeloma cells 79
Figure 24 Combinatorial effect of OSU-03012 and imatinib
mesylate on indicated molecules of signaling pathways 80
Figure 25 Western blotting analysis of time-course treatment with imatinib mesylate and OSU-03012 on U266 cells 81
Figure 26 Compounds targeting alternative pathways including p38 MAPK, histone deacetylase, AMPK and STAT3 are
beneficial for lymphoid malignancies 82

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