MPT0E028在人類大腸直腸癌與B細胞淋巴癌之抗癌機轉探討

Evaluation of the anticancer mechanisms of MPT0E028 in human colorectal cancer and B-cell lymphoma

黃瀚立(Han-Li Huang)

指導教授 ： 鄧哲明 ； 潘秀玲

國立臺灣大學/醫學院/藥理學研究所/博士(2015年)

https://doi.org/10.6342/NTU.2015.01388

摘要

隨著人民平均壽命延長及生活習慣的改變，癌症發生率仍持續上升，根據台灣衛生福利部國民健康署統計，癌症已為國人十大死因之首達三十年。為有效治療癌症，藥物開發在癌症領域中仍是相當重要的課題，其中組蛋白去乙醯酶(histone deacetylase, HDAC)為近期相當重要的藥物作用標的。本實驗室和台北醫學大學劉景平教授及潘秀玲副教授合作發展一個新穎的組蛋白去乙醯酶抑制劑MPT0E028，本篇論文即在探MPT0E028在人類大腸直腸癌及B細胞淋巴癌之抗癌機轉。
本篇論文第一部分，我們著重在探討MPT0E028在人類大腸直腸癌中的抗癌機轉及HDAC抑制效果。MPT0E028可以抑制許多癌細胞的生長，尤其對於HCT116細胞最為敏感。相對於第一個被FDA認可的HDAC抑制劑SAHA，MPT0E028可產生較強的細胞凋亡作用及HDAC抑制效果。在HCT116異體移植體內實驗中，MPT0E028可延緩並抑制腫瘤生長，相對於SAHA也具有較強的抑癌效果。
本篇論文第二部分，我們著重在探討MPT0E028在人類B細胞淋巴癌中的抗癌機轉及MPT0E028作用下，HDAC及Akt之間的關係。根據kinome diversity screen實驗結果發現，MPT0E028具有可直接接合並抑制Akt的能力;而我們也發現，HDAC及Akt皆對MPT0E028所引發的細胞凋亡作用具有貢獻，並且為獨立作用，並顯示相對於SAHA具有較強的效果。除體外實驗，B細胞淋巴癌動物模式體內實驗中也發現MPT0E028可以延長存活率並且抑制腫瘤生長。
綜合而言，我們的結果顯示MPT0E028具獨特性而有潛力成為癌症治療的新選擇。

關鍵字

MPT0E028 ； 組蛋白去乙醯酶(HDAC) ； Akt ； 大腸直腸癌 ； B細胞淋巴癌 ； 細胞凋亡

並列摘要

The incidence rate of cancer is increasing as more people live to an old age and as lifestyle changes. According to Health Promotion Administration, Ministry of Health and Welfare in Taiwan, cancer has been the first place of ten leading deaths for thirty-two years. In order to cure cancer efficaciously, drug development is still an important issue in cancer therapy. Histone deacetylase inhibitor (HDAC) has been an important drug target in recent years. Our lab cooperates with Professor Jing-Ping Liou (Taipei Medical University) and Associate Professor Shiow-Lin Pan (Taipei Medical University) to develop a novel HDAC inhibitor MPT0E028. In this thesis, we investigated the anticancer mechanism of MPT0E028 in human colorectal cancer and B-cell lymphoma.
In the first part of this thesis, we focus on the antiproliferation effect and the anti-HDAC potency of MPT0E028 in human colorectal carcinoma. MPT0E028 can inhibit a panel of cancer cells, especially most potent in HCT116 cells. MPT0E028 can induce stronger apoptosis effect and HDAC enzyme inhibition in vitro compared to SAHA, the first therapeutic HDAC inhibitor approved by FDA. HCT116 xenograft tumor growth was delayed and inhibited under treatment of MPT0E028 in vivo, which also showed a better antitumor efficacy than SAHA.
In the second part of this thesis, we focus on the antitumor effect of MPT0E028 in human B-cell lymphoma and the relationship between HDACs and Akt under the treatment of MPT0E028. According to kinome diversity screen data, MPT0E028 was found to exhibit direct Akt targeting ability. We revealed that both its inhibitory activity on HDAC and Akt contribute to MPT0E028-induced apoptosis, which functioned independently and showed stronger effect than SAHA. Besides in vitro experiment, in vivo study also showed that MPT0E028 may prolong the survival rate and inhibit tumor growth in B-cell lymphoma model.
Taken together, our results demonstrated that MPT0E028 has unique properties and may be a potential and promising anti-cancer therapeutic option.

並列關鍵字

MPT0E028 ； histone deacetylase (HDAC) ； Akt ； colorectal cancer ； B-cell lymphoma ； apoptosis

參考文獻

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