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標題: | 探討天然物Aciculatin與小穗苧麻素衍生物YXM110之抗癌機轉 Evaluation of mechanisms underlying anticancer activity of Aciculatin and YXM110 in human cancer cells |
作者: | Chin-Yu Lai 賴清裕 |
指導教授: | 鄧哲明(Che-Ming Teng),潘秀玲(Shiow-Lin Pan) |
關鍵字: | Aciculatin,YXM110,結腸直腸癌,非小細胞肺癌,細胞凋亡,自噬作用,p53,CK2-alpha, Aciculatin,YXM110,colorectal cancer,non-small cell lung cancer,apoptosis,autophagy,p53,CK2-alpha, |
出版年 : | 2013 |
學位: | 博士 |
摘要: | 根據衛生署的統計資料,惡性腫瘤連續30年蟬聯國人的第一死因,其中,氣管、支氣管及肺癌和結腸直腸癌又高居癌症死因的第一位和第三位。當腫瘤已經無法藉由手術移除,或是發生轉移時,給予全身性的化療藥物以及標靶藥物可增加病人的存活率。
細胞不受控制的生長、躲避免疫反應、抵擋計畫性死亡以及轉移的能力,是造成癌細胞不正常增生的主因。而目前的癌症藥物仍以化療藥物為主,標靶藥物做為合併使用以治療轉移的癌症。在研發癌症的用藥中,常以自然界之中草藥成分作為新藥開發的來源,希望能從中找到抑制腫瘤細胞生長的化合物。在本篇論文中,我們探討從天然物中萃取或合成之抗癌化合物,其作用機轉以及發展成為治療藥物的可能性。 Aciculatin是由弘光大學陳建志教授的研究團隊,從植物燈豎朽及竹節草中所萃取出來之天然化合物,雖發現其具有抗癌作用,但其詳細機轉尚未被研究。我們在結腸直腸癌以及非小細胞癌的細胞株HCT116和A549細胞中,觀察到aciculatin 可在短時間內大量引起p53的累積,並活化下游的蛋白質p21和PUMA造成細胞生長抑制和細胞凋亡作用。實驗也證實aciculatin 所引起之p53的累積,和MDM2的轉錄減少相關,且較不造成DNA損害。在小鼠的異體移植模式中,aciculatin 也可有效抑制HCT116腫瘤的生長且不引起明顯的毒性。在目前的癌症治療中,p53的活化和MDM2的抑制是影響細胞生長和促進細胞凋亡之重要路徑,aciculatin可在不引起基因毒性下,透過抑制MDM2轉錄而造成p53的活性,實屬一個難得的抗癌化合物,值得繼續修飾研發。 Cryptopleurine是普遍存在於Asclepiadaceae和Moraceae科植物中的生物鹼,主結構為phenanthroquinolizidine,已被證實對於多株人類癌細胞有顯著的抑制作用。北卡羅萊納大學教堂山分校之李國雄院士團隊,基於此結構合成了一系列YXM衍生物,期能篩選出具有抗癌潛力且較無副作用之化合物。在YXM衍生物中,YXM110特別對於多株人類癌細胞皆展現了最佳的抑癌效果,其在HCT116細胞株中GI50更低至3 nM。藉由細胞實驗證實YXM110可在早期抑制細胞生長,晚期促細胞凋亡。目前發現YXM110可降低與細胞生長相關之蛋白質生合成,並且引起具缺陷的細胞自噬而造成細胞死亡,這些機轉也在小鼠異體移植模式中被證實。在抗藥性的研究中也發現YXM110仍可有效抑制抗藥性細胞株之生長,並且其抑制4E-BP1的能力也幫助抵擋因缺氧造成的抗藥性。另外,也看到YXM110具有抑制CK2酵素活性和表現的作用,本篇論文也觀察到CK2在細胞凋亡和細胞自噬中有顯著角色。目前YXM110在活體中的最高容忍劑量以及藥物動力學數值也已評估完成,正在透過與李院士團隊的合作,期能發展出更具藥效及安全性的YXM110修飾結構,有潛力成為可繼續研發之候選藥物。 Malignant tumor has been the major cause of death in Taiwan for the recent 30 years and the incidence of lung cancer and colorectal cancer are the first place, and the third place respectively. Until now, researchers are still seeking for better cancer therapy. Cancer cells obtain various immortal abilities such as sustaining proliferative signaling, evading growth suppressors, resisting cell death and activating invasion and metastasis. When tumors are unable to be removed surgically or already undergo metastasis, systemic chemotherapy and targeted therapy become crucial for patient’s survival. Natural products have always been a profuse database for developing new chemo agents, thus modification from natural compounds which exhibit potent antitumor activity could be an effective strategy. In this thesis, we aim to discover and study the promising anticancer agents from natural products. Aciculatin is a natural compound isolated from the medicinal herb, Elephantopus scaber Linn and Chrysopogon aciculatus by the team of Prof. Chien-Chih Chen from Department of Biotechnology, Hungkuang University. This study is the first to prove that aciculatin induces cell death in human cancer cells and HCT116 mouse xenografts due to G1 arrest and subsequent apoptosis. The primary reason for cell cycle arrest and cell death was p53 accumulation followed by increased p21 level, PUMA expression, and induction of apoptosis. Aciculatin is also proved to induce p53 accumulation via MDM2 mRNA depletion without apparent genomic toxicity. Compared to the current chemotherapy which induce p53 through DNA damage, aciculatin exhibits higher safety therefore this compound is worthy to be further modified and developed. Cryptopleurine is a phenanthroquinolizidine alkaloid purified from Cynanchum paniculatum which shows excellent antitumor activity. Prof. Kuo-Hsiung Lee from Natural Product Research Lab (NPRL) in UNC at Chapel Hill has synthesized a series of compounds named YXM based on cryptopleurine. The results showed that YXM110 exhibited greatest activity against human colorectal cancer cell line HCT116; it induced cell growth inhibition in early stage and apoptosis in late stage. The anticancer mechanisms of YXM110 could be protein synthesis inhibition and autophagy regulation. YXM110 also exhibited anticancer effects in drug-resistant cell lines, and decreased levels of 4E-BP1 which is correlated with hypoxia-induced resistance. Moreover, YXM110 was found to inhibit the kinase activity and protein levels of CK2α, which is proved to regulate apoptosis and autophagy pathways. YXM110 shows the in vivo potency in xenograft model and the pharmacokinetics and toxicity are also confirmed. The NPRL will keep optimizing the YXM110 structure. Hope this lead compound could be modified to a drug candidate with better anti-tumor activity and safety. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17640 |
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