非傳統化學藥物治療惡性B淋巴球疾病：針對p38 MAPK, Akt 路徑或histone deacetylase的藥物機轉研究

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题名:	非傳統化學藥物治療惡性B淋巴球疾病：針對p38 MAPK, Akt 路徑或histone deacetylase的藥物機轉研究 Treating B-cell lymphoid malignancies with non-conventional chemotherapeutic agents: study of compounds targeting p38 MAPK, Akt pathways or histone deacetylase
作者:	白禮源
贡献者:	臨床醫學研究所博士班
关键词:	惡性淋巴球疾病;骨髓瘤;p38 MAPK;Akt;組蛋白去乙醯酶 lymphoid malignancy;myeloma;p38 MAPK;Akt;histone deacetylase
日期:	2011-05-17
上传时间:	2011-10-17 16:54:43 (UTC+8)
出版者:	中國醫藥大學
摘要:	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.
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