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研究生:高明
研究生(外文):Ming Gao
論文名稱:抗癌新藥OSU-03012作為治療肝細胞癌藥物可行性之研究
論文名稱(外文):Characterization and Evaluation of a Novel Anticancer Drug, OSU-03012, As a Potential Therapeutic Agent for Hepatocellular Carcinoma
指導教授:鄭安理鄭安理引用關係
指導教授(外文):Ann-Lii Cheng
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:144
中文關鍵詞:肝細胞癌細胞自噬活性氧化物
外文關鍵詞:Hepatocellular carcinomaautophagyreactive oxygen species (ROS)
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肝細胞癌(hepatocellular carcinoma, HCC)在全世界是第五大常見癌症,高居因癌症死亡原因的第三位。每年全世界約有500,000 至1,000,000 新病例的發生,造成約600,000例的死亡。肝癌也是台灣最常見的癌症之一。根治性手術治療只適合用於15%至25%的病人。大部分的病人都在相當短的時間內,因原位或轉移的腫瘤而死亡。全身性化學治療因為副作用太大,而無法成為治療肝癌的標準治療。因此,尋求有效且副作用低的藥物治療,對於肝細胞癌的治療是非常急切的一個課題。

基於對肝細胞癌分子生物機制日趨深入的了解,一些重要的細胞內信息傳導路徑,例如Ras/Raf/MEK/ERK 信息傳導路徑 和 PI3K/Akt/mTOR 信息傳導路徑,已經被發現與肝細胞癌的發生和惡化有著密切的關連。針對這些失調的信息傳導路徑發展而來的癌症標靶治療(molecular targeted therapy, MTT),為肝細胞癌的治療帶來一線生機,發展有效的標靶治療藥物已是當務之急。

OSU-03012是cyclooxygenase (COX)-2抑制劑celecoxib的衍生物。已經被證實在許多的腫瘤細胞,包括前列腺癌細胞,胰臟癌細胞以及乳癌細胞中有誘發細胞死亡的作用。OSU-03012主要是經由抑制3-phosphoinositide-dependent kinase-1 (PDK-1)/Akt信息傳導路徑來誘發細胞的死亡。另外,OSU-03012也被證實在神經膠質瘤細胞中,經由抑制與PDK1/Akt 無關的信息傳導路徑來造成細胞的死亡。因此,OSU-03012可能是一個多重標靶抑制劑,在不同的細胞中,經由不同的機制造成細胞的死亡。

細胞自噬 (Autophagy)是細胞在養分不足等不適宜的生存環境下,所產生的細胞自我分解的反應。通過細胞自噬,細胞內的蛋白質及胞器被分解,再利用來維持細胞新陳代謝的恆定。細胞自噬的過程是將一部份的細胞質和細胞胞器包入被稱為autophagosome的雙層膜性結構,這些雙層膜性結構再與溶酶體融合形成autolysosome,被包入的蛋白質及胞器等即在autolysosome中被溶酶體水解酶水解。細胞自噬一般被認為是一種細胞自我防禦的手段,但是近年來愈來愈多的證據顯示,細胞自噬也是造成細胞死亡的一個重要機制。許多的腫瘤細胞在接受了抗癌藥物的治療之後,會出現自噬性細胞死亡(亦被稱為第二型程序性細胞凋零)的反應。
我們的研究發現OSU-03012在非常低的濃度下可抑制Huh7, Hep3B, 和HepG2三株肝癌細胞的生長。TUNEL染色及流式細胞儀的分析結果,顯示OSU-03012並沒有在肝癌細胞中,誘發凋亡性細胞死亡。在OSU-03012處理過的Huh7細胞中,凋亡性細胞死亡兩個最具代表性的生物指標,caspase-3 和 cleaved PARP也未能在西方墨點法中偵測到。流式細胞儀的分析結果,顯示OSU-03012在Huh7細胞中,明顯的增加了S-Phase細胞族群。MDC螢光染色以及電子顯微鏡的結果,顯示OSU-03012在Huh7細胞中,誘發了細胞自噬現象的產生。西方墨點法也證實了細胞自噬現象的一個重要生物指標MAP-LC3轉換現象的發生。利用干擾RNA抑制與細胞自噬發生有關的基因ATG5的表現,以及廣泛使用的細胞自噬抑制劑,3-MA,降低了OSU-03012在Huh7細胞中引發的細胞自噬及細胞毒性反應。動物實驗也顯示OSU-03012有效的抑制了Huh7腫瘤細胞在動物體內的生長。這些實驗結果証明OSU-03012在肝癌細胞中誘導的細胞自噬現象是一個細胞死亡的機制。

此外,我們進一步探討OSU-03012在肝癌細胞中誘發的自噬性細胞死亡的分子機制。利用流式細胞儀以及螢光顯微鏡證實了OSU-03012在Huh7細胞中,增加活性氧化物(ROS)的產生。大量的ROS可以通過caspase的活化導致凋亡性細胞死亡,但是在某些特定的生理環境下,ROS亦可以在不同的腫瘤細胞中導致自噬性細胞死亡。使用自由基的清除物NAC和tiron,降低了OSU-03012在Huh7細胞中誘發的細胞自噬及細胞毒性反應。我們也發現在Huh7細胞中,因為OSU-03012的處理而增加的 ROS, 會導致內質網壓力 (ER stress)的產生及ERK1/2的活化。利用干擾RNA抑制Bip (參與 ER stress反應的一個重要蛋白質)的表現,增加了OSU-03012在Huh7細胞中誘發的細胞自噬。相反地,在使Huh7細胞高度表現Bip之後,降低了OSU-03012引發的細胞自噬及細胞毒性反應,証明ER stress 是OSU-03012在Huh7細胞中誘發細胞自噬的主要原因之一,同時亦顯示Bip在OSU-03012誘發的細胞自噬性死亡過程中,具有保護性的作用。我們也發現在Huh7細胞中,抑制了ROS所導致的ERK1/2的活化,可以減少OSU-03012引發的細胞毒性。並且進一步証實ERK1/2的活化降低了p27kip1的蛋白質量。p27 kip1的減少可能是造成S-Phase細胞族群的增加的原因之一。我們亦發現OSU-03012也增加了兩個與G1/S transition相關的蛋白,cyclin A和CDK2,在細胞內的含量。

綜合以上結果,我們證實了OSU-03012在肝細胞癌中誘發自噬性細胞死亡而非凋亡性細胞死亡。ROS的產生是OSU-03012在肝細胞癌中誘發自噬性細胞死亡的主要原因之一。我們的研究闡明了OSU-03012在肝細胞癌中誘發細胞死亡的一個新的機制,同時為OSU-03012成為一個具有潛力的肝細胞癌標靶治療藥物提供了理論基礎。
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. The incidence of HCC is estimated to range from ranging 500,000 to 1,000,000 new cases annually, causing 600,000 deaths worldwide per year. Surgery with curative intent is achievable for only 15 to 25% of patients, and most patients die from locally advanced or metastatic disease in a relatively short period of time. To date, cytotoxic chemotherapy has not been a standard treatment for HCC.
With intensive research on the molecular biology of HCC, several important intracellular signaling pathways such as the Ras/Raf/MEK/ERK pathway and the PI3K/Akt/mTOR pathway have been identified as involved in the carcinogenesis and tumor progression of HCC. Recently, molecular targeted therapy, which acts on these dysregulated signal transduction pathways, has shown promise as a treatment for advanced HCC. Development of novel agents to enhance the effectiveness of treatment is mandatory.
OSU-03012 is a derivative of celecoxib, a cyclooxygenase (COX)-2 inhibitor which has been shown to induce cell death in various types of cancer cells, including prostate cancer, pancreatic cancer, and breast cancer. The mechanism of action is presumably through inhibition of the 3-phosphoinositide-dependent kinase-1 (PDK-1)/Akt signaling pathway. In addition to PDK-1/Akt signaling inhibition, OSU-03012 might also have effects on other important signaling pathways. For example, OSU-03012 has been reported to cause a PDK1/Akt-independent cell death in glioma cells. These findings suggest that OSU-03012 might be a multi-targeted inhibitor which exerts its functions in a cell type-dependent manner.
Autophagy has been recognized as a cellular catabolic degradation response to starvation or stress where cellular proteins and organelles are engulfed, digested and recycled to maintain cellular metabolism. The process of autophagy starts by sequestering a portion of the cytoplasm and intracellular organelles in a double-membrane-bound structure known as the autophagosome. These autophagosomes subsequently fuse with lysosomes to form autolysosomes, in which the sequestered contents are degraded by lysosomal hydrolases. Recent studies demonstrated that autophagy also has an active role in cell death. Autophagy or autophagic cell death, also known as type II programmed cell death, has been shown to be a response to various anticancer therapies in many kinds of cancer cells.
In this study, we showed that OSU-03012 inhibits growth of Huh7, Hep3B, and HepG2 cells within a low micromolor range. TUNEL assay and flow cytometry analysis indicated that no apoptotic cell death was induced by OSU-03012 treatment. Active caspase-3 and cleaved PARP, two biochemical markers of apoptosis, were undetectable by Western blot analysis in OSU-03012-treated Huh7 cells. OSU-03012 induced a significantly increased S-phase population in Huh7 cells. Interestingly, OSU-03012 induced autophagy in Huh7 cells, evidenced by MDC staining, electron microscopy image and Western blot analysis of MAP1-LC3, an important marker of autophagy. OSU-03012-induced autophagy as well as cytotoxicity was partially reversed by silencing ATG5, a gene involved in autophagy, or 3-MA, a widely used autophagy chemical inhibitor. The xenograft tumor model demonstrated that OSU-03012 suppressed Huh7 tumor growth. These findings suggest that autophagy is a mechanism which contributes to the in vivo cytotoxic effect of OSU-03012.
We next demonstrated that OSU-03012 induced reactive oxygen species (ROS) generation by using H2DCFDA-based flow cytometry and florescence microscopy detection. While high levels of ROS often induce apoptotic cell death through caspase activation, ROS cause autophagic cell death in different cancer cells under certain physiological conditions. The ROS scavengers N-acetylcysteine (NAC) and tiron abrogated OSU-03012-induced autophagy and subsequent cytotoxicity. We found that OSU-03012 increased ROS accumulation which in turn induced ER stress and ERK1/2 activation. Knockdown of Bip, an ER stress marker, enhanced OSU-03012-induced autophagy, while overexpression of Bip decreased OSU-03012-induced autophagy and subsequent cytotoxicity, suggesting that ER stress is involved in OSU-03012-induced autophagic cell death and Bip protects the cells from OSU-03012-induced cell death.
In parallel, we found that inhibition of ERK1/2 activated by ROS accumulation reversed OSU-03012-induced cytotoxicity in Huh7 cells. We showed that activated ERK1/2 triggered a decrease in the p27 kip1 protein level, which may result in arrested or prolonged S-phase cells. We further demonstrated that the expression of cyclin A and CDK2, two G1/S-related proteins, were increased by OSU-03012.
In conclusion, our results show that the orally bioavailable drug OSU-03012 induces autophagic but not apoptotic cell death in HCC, and that this autophagy-inducing activity is in part related to ROS accumulation. This study demonstrates a novel biological effect of OSU-03012 which supports its clinical potential as a component of therapeutic strategies for HCC.
CONTENTS

Abstract in Chinese........................ 1
Abstract in English........................ 4
Chapter 1 Introduction....................... 8
Hepatocellular Carcinoma...................... 9
OSU-03012............................ 20
Purpose of this study......................... 24
References............................. 26
Chapter 2 OSU-03012 induces autophagy in HCC cells.......... 34
Abstract.............................. 35
Introduction ............................ 36
Materials and Methods........................ 43
Results.............................. 49
Discussion............................. 55
References............................. 58
Figures and figure legends...................... 65
Chapter 3 The mechanisms of OSU-03012 biological effects: ROS accumulation and ERK activation are involved in OSU-03012-induced autophagic cell death........................ 87
Abstract.............................. 88
Introduction............................ 89
Materials and Methods........................ 97
Results.............................. 101
Discussion............................. 107
References.............................. 113
Figures and figure legends....................... 121
Chapter 4 Summary and future directions............... 141
Appendix.............................. 144
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