癌症多年來皆位居國人十大死因之首，其相關研究一直是許多大型國家計劃之重點發展項目。因此，對於了解癌症進行、癌症轉移的分子機制，以及研發新穎且更有效的抗癌藥物，都是當前刻不容緩的任務。天然物一直是人類最大的藥物來源，接近 70% 的臨床抗癌藥物皆是源自天然物或其衍生物，如紫杉醇、喜樹鹼衍生物及長春花鹼等。本團隊一向致力於天然藥物之研究。近年來我們自台灣特有種粗毛金星蕨中分離出 protoapigenone (WYC-02)，此為一新型之天然抗癌黃酮類化合物。子計畫一與子計畫二的計畫主持人吳永昌教授及吳志中教授已證實 WYC-02 之抗腫瘤活性與壓力激?有關，如 p38MAPK 和JNK，而且 WYC-02 可以經由抑制 ATR/FANCD2 路徑，進而抑制 DNA 損傷反應。根據WYC-02 的分子結構與活性分析，本團隊設計並合成其衍生物 WYC-0209，結果顯示它和WYC-02 具有同樣的效果，並顯現更有效的抑制腫瘤活性。子計畫三的主要目的，就是探討與 WYC-0209 及衍生物相關的分子作用機制與體內生物活性。我們將進行在體外和體內生物實驗來達成這一目標。此外我們將使用已認證化的細胞轉移與細胞凋亡陣列來闡明 WYC-0209 及其衍生物之分子機制。此整合行計畫將會證明開發和商業化 WYC-0209 及其衍生物，以作為新穎抗癌藥物是非常可行的。而進一步研究會影響新化合物和新分子特定生物活性的分子機制，更可以作為發展癌症患者個人化醫療的分子標的。
Cancer is a leading cause of death in Taiwan over the past years, and has been the focus of many national research programs. Thus, understanding the molecular mechanisms of tumor progression and metastasis, and development of novel anti-cancer drugs is urgently needed. The natural products have been the largest source of drugs for humans with nearly 70% of the clinical anti-cancer drugs being derived from natural products or their derivatives such as paclitaxel (taxol), camptothecin derivative, irinotecan (CPT-11), and vinca alkaloids among others. Our team has continuously been committed to the research of natural medicine. In recent years, we isolated a novel type of natural anti-cancer flavonoids: protoapigenone (WYC-02) from Macrothelypteris torresiana, which is commonly used as folk medicine in Taiwan. It has been demonstrated by Projects 1 and 2 leaders (Drs. Yang-Chang Wu and Chin-Chung Wu) that the antitumor activity of WYC-02 is related to stress kinases such as p38MAPK and JNK, and WYC-02 can inhibit DNA damage signaling through ATR/FANCD2 inactivation. Furthermore, based on the structure-activity relationship (SAR) study of WYC-02, we designed and synthesized WYC-0209, which has also showed same effect but with more potent inhibitory activity. The main goal of Project 3 is to understand the molecular mechanisms and in vivo biological activities of WYC-0209 and its derivatives. We will conduct both in vitro and in vivo biological assays to achieve this goal. Furthermore, we will elucidate molecular mechanism of WYC-0209 and its derivatives using non-biased approach such as metastasis and apoptosis arrays. Together with the outcomes from Projects 1 and 2, development and commercialization of WYC-0209 and its derivatives as novel anti-cancer drugs are feasible in the near future. In addition, understanding the molecular mechanisms that affect specific biological activities of the identified novel compound and the novel molecules identified in this project could also serve as the molecular signatures for development of personalized medicine for cancer patients.
