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Title: | 探討 DYZ-2-90 和 MPT0G030 在人類大腸直腸癌細胞中之抗癌機轉 Evaluation of mechanisms underlying anticancer activity of DYZ-2-90 and MPT0G030 in human colorectal cancer cells |
Authors: | Li-Ting Wang 王俐婷 |
Advisor: | 鄧哲明(Che-Ming Teng),潘秀玲(Shiow-Lin Pan) |
Keyword: | 大腸直腸癌,微管,HDAC,細胞分化,DYZ-2-90,MPT0G030, colorectal cancer,microtubule,HDAC,cell differentiation,DYZ-2-90,MPT0G030, |
Publication Year : | 2014 |
Degree: | 博士 |
Abstract: | 台灣衛生福利部國民健康署統計資料顯示,惡性腫瘤已居國內十大死因之首近三十多年,其中大腸直腸癌發生率已躍居癌症的第一位;另外,根據世界衛生組織 WHO 公佈的 GLOBOCAN 統計,大腸直腸癌為世界上癌症死因中第三位。相對於其他癌症的發生病因,大腸直腸癌已確立明確的致病機轉:adenoma-carcinoma sequence,乃是一高度具有發生順序性的模式。本實驗室與美國北卡羅來納教堂山分校藥學系李國雄院士及臺北醫學大學藥學系劉景平教授合作,分別探討天然藥物衍生物 DYZ-2-90 和小分子藥物 MPT0G030 在大腸直腸癌中的抗癌機轉。
在腸癌細胞 HT-29 不正常增生的情況下,利用 DYZ-2-90 抑制細胞過度的生長。DYZ-2-90 是修飾自上品中藥丹蔘萃取成分 neo-tanshinlactone 的一個新穎的開環化合物,可直接和微管結合抑制微管的聚合作用,使細胞分裂中重要的紡錘絲去聚合。然而,紡錘絲結構的崩解不僅使細胞週期停滯於 G2/M 期,也使得原本微管上的訊息傳遞分子 ERK 持續活化,用以維持細胞存活的訊號,避免細胞凋亡以進行細胞的自我修復;而在藥物作用的後期,因細胞長期停滯於 G2/M 期,對細胞反而累積成為一股 mitotic stress 刺激 JNK 活化,使受到藥物損傷的細胞經過活化 caspase 走向細胞凋亡。因此在 DYZ-2-90 的作用之下,癌細胞的命運由兩條互相競爭的路徑來決定,可說是 Mitotic exit threshold 與 Death threshold 之間的競爭,也可說是 ERK (細胞生存、細胞週期停滯) 和 JNK (細胞凋亡) 路徑間的競爭。 另一方面,利用 HDAC 抑制劑 MPT0G030 引導腸癌細胞 HT-29 進行正常腸細胞的生命週期,走向細胞分化與細胞凋亡。MPT0G030 是一個有效的抗癌藥物,對許多不同人類癌細胞株都有很好的毒殺作用。不僅可以有效抑制許多腫瘤組織中會過度表現的 class I HDACs,在人類大腸直腸癌細胞中也可活化 PKCδ,促使 E-cadherin 重新分佈、改變細胞形態,使癌細胞分化並走向死亡;並且也證明 HDAC1 會調控 PKCδ 的活化。在 HT-29 人類腫瘤異體移植的抗癌作用模型中,也證實了 MPT0G030 對 HDAC1 和 PKCδ 的作用與細胞實驗結果一致。 綜合以上兩部分的論文結果顯示,DYZ-2-90 是一個有效的去微管抑制劑,而 MPT0G030 是一個有效的 class I HDAC 抑制劑,分別抑制腸癌中失控的細胞生長及促進細胞分化,兩者都俱有發展為人類大腸直腸癌化學治療藥物的潛力。 Latest statistics reported by Taiwan’s Health Promotion Administration, malignancy has been the major causes of death in Taiwan for 30 years; among those, colorectal cancer is the first-leading cause of cancer deaths. Meanwhile, colorectal cancer is the 3rd most common cancer worldwide. In contrast to other cancers, development of colorectal cancer is an ordered event of genetic and epigenetic changes that called adenoma-carcinoma sequence. Our laboratory cooperates with Dr. Kuo-Hsiung Lee (Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, USA) and Dr. Jing-Ping Liou (School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan) to evaluate the anticancer effect and the underlying mechanisms of DYZ-2-90 and MPT0G030 in human colorectal cancer, respectively. In situations of aberrant hyperproliferation, DYZ-2-90 targets to the mitotic spindles, the critical structure of cell mitosis, and leads to microtubule depolymerization in HT-29 cells. DYZ-2-90 is a novel ring-opened compound modified from neo-tanshinlactone isolated from Chinese medicinal herb Tanshen. It binds directly to microtubules and rapidly suppresses microtubule polymerization in human colorectal cancer cells. Thus, the alteration of mitotic spindle organization changes the scaffolding properties of microtubules, which induces strong and sustained ERK activation and leads to mitotic arrest. Prolonged ERK activation and cyclin B degradation contributes to maintain the cell mitotic state and protect cells from apoptosis, but meanwhile provides more time to accumulate mitotic stress/cell death signals. Then, the cell apoptosis is triggered by anti-apoptotic protein Mcl-1 degradation and JNK activation, which breach the death threshold. The cell fate of mitotic arrest cells is dictated by two competing networks: one is the cytoprotective ERK pathway, and the other is stressed-related JNK pathway. Whereas, MPT0G030, a HDAC inhibitor, redirects colorectal cancer cells (HT-29 cells) to normal colonic life cycle to undergo cell differentiation and cell apoptosis. MPT0G030 is a potent HDAC inhibitor that showed broad-spectrum cytotoxicity against various human cancer cell lines. It not only effectively inhibits class I HDACs, which are overexpressed in many malignant neoplasms, but also redistributes E-cadherin and activates PKCδ, which is linked to cell apoptosis and differentiation. Further, activation of PKCδ is demonstrated to be modulated through HDAC1. Collectively, MPT0G030-induced PKCδ participates in cell apoptosis and concomitantly promotes differentiation of colon cancer cells through E-cadherin redistribution and changes in cell morphology. In this thesis, our results indicate that both DYZ-2-90, a novel microtubule-destabilizing agent, and MPT0G030, a class I HDAC inhibitor, have great potential as new drug candidates for colorectal cancer therapy. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57110 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 藥理學科所 |
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