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Title: | 新穎HDAC抑制劑在非小細胞肺癌與腸炎之研究 Effects of Novel HDAC Inhibitors on Non-Small Cell Lung Cancer and Colitis |
Authors: | Ruo-Yu Tseng 曾若瑜 |
Advisor: | 陳青周 |
Keyword: | 新穎HDAC抑制劑, Novel HDAC Inhibitor, |
Publication Year : | 2015 |
Degree: | 碩士 |
Abstract: | EGFR activating mutation在亞洲區非小細胞肺癌病患約占60%,EGFR-TKI如gefitinib與erlotinib可有效治療此類EGFR過度活化之病患,但通常約一年後會產生acquired resistance;為進一步探討acquired resistance之機轉,我們建立gefitinib resistance細胞株HCC827/IR,外觀具mesenchymal form 伴隨著E-cadherin 之downregulation和vimentin 之upregulation。 本實驗中,新穎HDAC抑制劑JMF3086可增加E-cadherin及減少vimentin 的表現。併用JMF3086 與gefitinib可克服gefitinib抗藥性並誘發細胞凋亡;併用JMF3086 與化療藥物cisplatin亦可以抑制細胞生長並誘發細胞凋亡。因此,JMF3086併用gefitinib或cisplatin具有潛力應用於gefitinib抗藥性之非小細胞肺癌病患。 發炎性腸道疾病(Inflammatory bowel disease) 包括克隆氏症(Crohn’s disease, CD)及潰瘍性結腸炎(Ulcerative colitis, UC),病因包括免疫系統失衡、環境因子及遺傳因素,目前藥物僅能控制疾病未能完全治癒。本實驗中,statin-SAHA conjugated 之JMF compound在DSS動物模式,具有預防及治療潰瘍性結腸炎之效果。 Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Activating mutation of epidermal growth factor receptor (EGFR) is found in NSCLC and occurs frequently in East Asian. EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib have exhibited significant effect on EGFR-mutant NSCLC. Nevertheless, patients develop acquired resistance to TKI. To further explore the mechanism of acquired resistance in NSCLC, we developed gefitinib resistance cell line HCC827/IR that showed mesenchymal phenotype accompanied with low expression of E-cadherin and high expression of vimentin. In our study, a novel polypharmacological HDAC inhibitor, JMF3086 could induce E-cadherin and decrease vimentin expression. Here, we showed that combination of gefitinib and JMF3086 overcame gefitinib resistance and induce apoptosis. Patients with EGFR mutation have longer survival after second-line treatments with platinum-class drug cisplatin. We therefore combined cisplatin and JMF3086 and showed that their combination led to growth inhibition and apoptosis. Therefore, JMF 3086 combined with gefitinib or cisplatin might be potential therapies to overcome gefitinib resistance in NSCLC. Inflammatory bowel disease (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), is a complex disease mediated by genetic, immune, and environmental factors. Recently, medications to cure IBD is limited while animal models of intestinal inflammation provide a good way to further investigate the cause of IBD and possible medication. In this study, JMF compound, statin-SAHA conjugated compound had promising effect on prevention and treatment of IBD by using DSS-induced acute colitis mouse model. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52754 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 藥理學科所 |
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ntu-104-1.pdf Restricted Access | 11.23 MB | Adobe PDF |
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