臺灣大學: 醫學檢驗暨生物技術學研究所林亮音; 許駿;歐大諒鄭宇哲Cheng, Yu-CheYu-CheCheng2013-04-162018-07-062013-04-162018-07-062012http://ntur.lib.ntu.edu.tw//handle/246246/257803Sorafenib是一個針對晚期肝癌的標準治療藥物，也是第一個被證實可以有效地提升晚期肝癌存活率的藥物。Sorafenib最早是在一個發展Raf磷酸激酶抑制劑的計畫中被發展出來的藥物，然而過去的許多研究指出，Sorafenib有許多「標靶外作用」﹝off-target effects﹞與其抗癌療效及抗藥性的產生有密切關係。我們實驗室之前在Sorafenib對肝癌細胞的研究中發現，Sorafenib可以在mRNA及蛋白的層面抑制肝癌細胞週期素E1的表現，而肝癌細胞產生抗藥性時Sorafenib抑制週期素E1表現也隨之變差，且當利用siRNA去降低週期素E1的表現時，可以有效地促使Sorafenib誘導具抗性的肝癌細胞走向凋亡。為了更深入探討週期素E1在Sorafenib抗藥性中扮演角色，及臨床應用的可行性。我的研究首先在肝癌細胞內大量表現週期素E1，發現大量表現週期素E1時會有效阻止Sorafenib誘導肝癌細胞走向凋亡。其次，為了探討臨床上的應用，發現使用Flavopiridol(一個細胞週期抑制劑)合併Sorafenib時可以協同增強（synergistic effects）肝癌細胞走向細胞凋亡、與抑制肝癌細胞生長等現象。此一作用可能與肝癌細胞中Bcl-XL及Mcl-1的表現被抑制有關。最後，動物實驗證明Sorafenib合併Flavopiridol確實可以有效抑制肝癌細胞腫瘤的形成。綜合以上結論，週期素E1有潛力可以當作肝癌的治療標的，或者是療效以及預後的參考，而Sorafenib合併使用Flavopiridol也是一個有潛力的治療方式。Sorafenib is a drug for standard systemic therapy in patients with advanced HCC (hepatocellular carcinoma), and it is also the first drug with survival benefits. Although sorafenib was originally designed as a specific Raf kinase inhibitor, we and other investigators have found many off-target effects of sorafenib that may have significant implications regarding its anti-tumor activity and resistance mechanisms of sorafenib in HCC cells. Our laboratory has found, for example, that sorafenib can down-regulate Cyclin E1 expression in mRNA and protein levels in various HCC cell lines. The resistance of HCC cells to sorafenib is associated with higher basal levels of Cyclin E1 expression and failure by sorafenib to cause down-regulation. Knockdown of Cyclin E1 expression by siRNA reversed the resistance of HCC cells to sorafenib in terms of cell apoptosis induction. In the present study, we sought information for a more in-depth discussion of the role Cyclin E1 plays in sorafenib-resistant HCC, with particular attention to feasibility and clinical applications. In the study, I promoted the over-expression of Cyclin E1, and this was effectively able to prevent apoptosis induction by sorafenib in HCC. In exploring the clinical application of a combination of sorafenib and flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, I found that it synergistically inhibited cell growth and induced apoptosis in HCC cells. The synergistic efficacy was associated with the suppression of Bcl-XL and Mcl-1 expression in HCC cells. Finally, sorafenib combined with flavopiridol inhibited tumor growth significantly better than either agent did individually in the xenograft models. In conclusion, the results indicate that Cyclin E1 might be a potential target for cancer therapy and a candidate marker for disease diagnosis or prognosis. In addition, sorafenib combined with flavopiridol could be of potential therapeutic value in the future.2869414 bytesapplication/pdfen-US肝癌標靶外作用sorafenib週期素E1flavopiridolHepatocellular carcinoma (HCC)off-target effectsCyclin E1[SDGs]SDG3thesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/257803/1/ntu-101-R98424031-1.pdf