一個新穎的Indole-3-Carbino衍生物之抗癌分子機制與結構優化

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Title:	一個新穎的Indole-3-Carbino衍生物之抗癌分子機制與結構優化 Anti-Tumor Mechanisms and Structural Optimization of a Novel Indole-3-Carbinol Derivative
Authors:	翁靖如
Contributors:	中國醫藥大學生物科技學系
Keywords:	Indole-3-carbinol;Antitumor agents
Date:	2009-07
Issue Date:	2010-09-01 17:53:47 (UTC+8)
Abstract:	癌症的罹患率與死亡率一直高居不下，不僅是全球所關注的問題，學、產界也投入大筆資金與時間去試圖找出癌症有關的治療或緩解。許多文獻證實細胞增殖及設定性凋亡間失衡與癌症的發生有密切關聯性。也因此人們經常以預防化學癌化方式，攝取蔬果中所含的植物化學物質，來避免細胞產生不正常增殖。甘藍菜中所含的Indole-3-carbinol (I3C)便是其一，但它的化學不安定，可能顯著降低I3C 的抗癌活性。筆者為找尋比I3C 的抗癌活性更好的藥物，已經以其為前導藥品作衍生而得到一系列的化合物並從藥理活性篩選出衍生物，A9 的毒殺癌細胞株能力最強。我們推測經過化學結構修飾，A9 有一百倍的活性改善是與前驅物，I3C 所誘發的細胞週期停滯與設定性凋亡的分子標靶相關。且從初步資料顯示，A9 表現的抗癌分子機制值得被探討。在此三年的計劃中，第一年我們將以I3C 為主體所研發的化合物，A9 進行與文獻已報導I3C 所涉及之訊息分子表現的細胞實驗，並且投與動物體內觀察其抗癌的分子標靶。且利用晶片去篩選出A9 可能影響的腫瘤抑制基因或致癌基因之調控，並以Real-time reverse transcription-PCR 去確認在microarray 上受到干擾的基因在mRNA 層面的表現與 Western blot 分析以確認。第二年再利用A9 為前導物，作構造上之優化，合成新一類的抗癌藥物且進行癌細胞的活性篩選。第三年將第二年所合成的一系列A9 衍生物，其中比A9 更具抗癌活性的化合物進行細胞實驗與動物模式探討可能誘發設定性凋亡之相關訊息機制，且配合晶片與Real-time reverse transcription-PCR 作更深入的探討。而以上不論是A9 或其更具顯著抗癌活性的衍生藥物，有關其活性與結構的探討及作用機制之討論，包含晶片的分析資料都可使我們對化學物質對抗癌症之間的關係更為瞭解，不僅可嘗試研發為臨床用藥，這些資訊更可成為日後設計其他相關新藥之用。 The incidence and mortality rate of cancer have become a global health problem. Basic scientists and clinicians are working together to better understand cancer biology in an effort to develop effective strategies for cancer treatment. It is now well understood that tumorigenesis results from the imbalance between cell proliferation and apoptosis. Thus how to reverse this imbalance constitutes the focus of many drug discovery projects, which have led to the discovery of many phytochemicals capable of suppressing aberrant cell proliferation by correcting dysregulated signaling pathways. The present proposal thus focuses on the mechanistic characterization and structural optimization of a novel derivative of indole-3-carbinol (I3C), a chemopreventive agent from cruciferous vegetables. In the PI』s laboratory, we have synthesized a series of I3C derivatives for pharmacological screening. Among these derivatives, A9 represents an optimal agent with 100-fold increase in the cytotoxicity against several cancer cell lines. Equally important, A9 overcomes the intrinsic chemical instability of I3C in acid. This chemical instability leads to lower antitumor potency and unpredictable pharmacokinetic behaviors of I3C in vivo. Our preliminary study indicates that the high antiproliferative potency of A9 was attributable to its ability to induce cell cycle arrest and apoptosis. Thus, mechanistic characterization and continued lead optimization represent the foci of this investigation. In the first year of this three-year project, we will prove our hypothesis that A9 mediates antiproliferative activities by sharing many signaling mechanisms with I3C. In addition to Western blot analysis of the effect of A9 on various signaling targets, the PI proposed to use microarray analysis to carry out gene expression profiling of A9 in tumor suppressor genes and oncogenes. Real-time reverse transcription-PCR in conjunction with Western blot analysis will be used to verify the gene alterations. In the second year, A9 will be used as the lead compound to establish a library of A9 derivatives. This library will be tested for cytotoxicity and undergo pharmacological screening against different biomarkers. In the third year, the optimal agent generated from the drug library will be tested against the previously identified molecular targets related to cell cycle control and apoptosis. Then, microarray and the Real-time reverse transcription-PCR will provide more information about the mode of mechanism of the optimal A9 derivative. In vivo antitumor potential of these novel agents will be further tested by different xenograft tumor models in nude mice. Overall, the aforementioned structure-activity analysis and mechanistic characterization of A9 will provide us further insights regarding the clinical use of this class of novel antitumor agents.
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