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標題: | 新穎HDAC抑制劑-MPT0G028在人類大腸癌細胞之抗癌機轉探討 Anticancer activity of the novel histone deacetylase inhibitor, MPT0G028, in human colorectal cancer cells in vitro and in vivo |
作者: | Chia-Hua Lee 李嘉華 |
指導教授: | 鄧哲明(Che-Ming Teng) |
關鍵字: | 大腸直腸癌,HDAC抑制劑,細胞凋亡,β-catenin, Colorectal cancer,HDAC inhibitor,apoptosis,β-catenin, |
出版年 : | 2013 |
學位: | 碩士 |
摘要: | 癌症自民國72年以來已連續30年蟬聯國人十大死因之首,而近年來,隨著飲食西化及診斷儀器的精進,使大腸直腸癌的發生率持續攀升。大部分的病患以手術切除可以治癒,然而術後的復發則使其死亡率居高不下。
許多文獻證實,癌症常伴隨異常高度表現的histone deacetylases (HDACs),而這樣的現象被發現是跟epigenetic的改變有高度關聯性。所以針對HDAC做為標的而發展的HDAC抑制劑在癌症的治療上是具有相當潛力的。本篇論文中,探討一個新合成的HDAC抑制劑MPT0G028在大腸直腸癌細胞上的抗癌機轉。 首先,篩選一系列以tetrahydroquinoline為結構基底所設計出來的HDAC抑制劑,發現人類大腸直腸細胞癌HCT-116細胞對MPT0G028的抑制效果有最好的反應。根據所觀察到的實驗結果,MPT0G028比FDA所核准的pan-HDAC抑制劑SAHA具有更好的細胞抑制生長、細胞毒殺和HDAC抑制能力。藉由fluorogenic HDAC assay kit,觀察到MPT0G028對於class I HDAC的活性抑制較為明顯。MPT0G028在HCT-116可以增加組蛋白H3乙醯化和HDAC被抑制的指標p21WAF1/CIP1蛋白表現,然而α-tubulin的乙醯化程度不明顯。進一步的實驗結果顯示,MPT0G028調控HCT-116的細胞凋亡,包括Sub G1期的增加及caspase 3、PARP的切割現象;並且在內生性細胞凋亡路徑上,增加pro-apoptosis蛋白Bak、Bim,減少BID proform及減少anti-apoptosis蛋白Bcl-2、Bcl-xL、Mcl-1。另外,MPT0G028抑制β-catenin蛋白及其上游蛋白Akt、磷酸化GSK-3β,以及下游蛋白cyclin D1、c-Myc、survivin。最後,在腫瘤移植的動物模式中也發現,MPT0G028可有效抑制腫瘤體積,且其低毒性對於動物的體重影響不大。總結而言,MPT0G028在人類大腸直腸癌細胞中可有效的抑制HDAC活性、促進細胞凋亡,並且抑制β-catenin和其上、下游蛋白的表現。 關鍵詞:大腸直腸癌、HDAC抑制劑、細胞凋亡、β-catenin Cancer has been the top of ten leading causes of death in Taiwan since 1982. In the decades, the incidence of colorectal cancer (CRC) has been increasing rapidly due to accompanying westernized diet and sophisticated diagnosis instruments. Although most patients are curable by surgery, recurrence of CRC is the main problem and cause of the high mortality rate. It has been reported that cancer progression is related to overexpression of histone deacetylases (HDACs), and the phenomenon was highly accordant with epigenetic change. Therefore, development of drugs that target on HDACs could be a promising strategy for the treatment of cancer. In the current study, we investigated the anti-cancer activity of a novel HDAC inhibitor, MPT0G028, on colorectal cancer cell lines. First, MPT0G028 showed the best anti-proliferative effect among a series of tetraquinoline derivatives in HCT-116 cells. According to observed results, MPT0G028 is more potent than the FDA-approved HDAC inhibitor, SAHA, as evidenced by cell growth inhibition, cytotoxicity, and better HDAC-inhibition activity. From the results of fluorogenic HDAC assay, MPT0G028 mainly targeted on class I HDACs. MPT0G028 increased the expression of acetyl-histone H3, p21, and to a less extent on acetyl-α-tubulin. Moreover, the data showed that MPT0G028 triggered apoptosis in HCT-116 cells, including Sub G1 induction and cleavage of caspase 3 and PARP. We also observed the upregulation of pro-apoptotic proteins (Bak and Bim) and the reduction of anti-apoptotic proteins (BID proform, Bcl-2, Bcl-xL, and Mcl-1). Moreover, MPT0G028 decreased the protein level of β-catenin and its upstream proteins (Akt and phospho-GSK-3β) as well as its downstream proteins (cyclin D1, c-Myc, and survivin). Finally, MPT0G028 inhibited tumor growth in a dose-dependent manner with low toxicity as evidenced by no obvious body weight loss in HCT-116 xenograft model. In conclusion, MPT0G028 inhibited HDAC activities, triggered apoptosis and down-regulated the expression of β-catenin as well as its up/down-stream proteins in CRC cancer cells. Key words: Colorectal cancer, HDAC inhibitor, apoptosis, β-catenin |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17463 |
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