Anti-cancer mechanism study of several active compounds in human prostate cancers

癌症占人類死亡疾病的第一位，其中，前列腺癌名列全球男性癌症的第三位，在北美及歐洲地區更為首位，而因目前台灣民眾的生活習慣愈來愈傾向西方歐美國家，前列腺癌更列入國家男性十大癌症死因之一。儘管前列腺癌發生率及威脅性如此高，但目前治療策略卻仍有限，賀爾蒙阻斷療法、放射線治療、手術直接切除、及化學療法是現今最常使用的前列腺癌治療方法。前列腺癌細胞依賴雄性素存活，若阻斷前列腺癌細胞接受雄性素，可有效縮小腫瘤，達到治療之效。然而，接受賀爾蒙療法一段時間後，會誘發雄性素不依賴型癌細胞產生，而使此種治療效果失效。另外，因為癌症轉移的特性，使手術切除也逐漸失去重要性。至於化療藥物在前列腺癌的治療上則一直沒有明顯的進展。因此，發展一種對癌細胞有特異性的化療藥物，可謂目前當務之急的任務。在這裡，我們選用PC-3這株雄性素不依賴型的人類前列腺癌細胞，來對各種系列的天然物與化學合成物，作抗癌作用的篩選及機轉的探討。另一方面，探究前列腺癌細胞的癌化作用與發展的過程，實為重要的抗癌研究基礎，針對此項，我們也嘗試去探討一個致癌物–N-methyl-N''-nitro-N-nitrosoguanidine (MNNG)，在前列腺癌細胞所引發的癌化作用過程裡有哪些重要的分子參與。因此，本論文第一部分為天然物cryptocaryone在雄性素不依賴型前列腺癌細胞PC-3的抗癌作用機轉的研究，cryptocaryone藉由引發死亡受體的自體聚集作用且分布在脂筏與非脂筏部分，去引發DISC複合體形成於細胞膜內側，進而將死亡訊息傳遞進細胞內，造成細胞凋亡的結果。第二部分為一個致癌物–MNNG，在PC-3分別能促進癌化作用與細胞死亡的作用機制探討。5Cancer plays first place of death in human diseases. Among these cancers, prostate cancer plays third place of global men’s cancers. As the lifestyle of Taiwanese is more similar to Western’s, the mortality of Taiwanese’s prostate cancer is higher than ever. Even so high mortality, prostate cancer therapy is still limited to hormone disruption therapy, radiation therapy, castration, and chemotherapy. Since prostate cancer is characteristics of dependending on androgen, hormone disruption therapy is an effective anti-cancer strategy. However, prostate cancer cells will develop to be androgen-independent, which conveys resistance to hormone therapy. Besides, prostate surgery is always limited according to the property of cancer metastasis. As for chemotherapy, there are some drawbacks such as effectiveness and toxicity. Therefore, the targeted strategy in prostate cancer therapy is so waiting developed as to solve these problems. Here, we tested several nature products and chemical compounds and furtherly identified the detailed anti-cancer mechanism in androgen-independent prostate cancer cell PC-3 on part-I and part-III. We hope the research can be served as a reference of developing targeted strategy. On part II, we investigated the different results and mechanisms of a carcinogen, MNNG at low and high dose in PC-3 cells, which is also an important basis on prostate cancer research. Part-I is about the anti-cancer mechanism of a nature product, cryptocaryone, in androgen-independent prostate cancer cell, PC-3. Cryptocaryone can induce death receptor clustering on lipid raft and non-lipid raft fractions to activate extrinsic apoptotic pathway. The detailed mechanism includes the formation of DISC complex and caspase-8 activation. Part-II is about the mechanism of low and high dose MNNG in androgen-independent prostate cancer cell PC-3. Low dose MNNG can activate NF