根據世界衛生組織 (WHO) 統計，2018年肺癌致死率居世界之冠，其中又以非小細胞肺癌 (NSCLC) 佔最大宗。造成肺癌發生的危險因子包括吸菸、輻射暴露、空氣汙染等，發酵食品與酒精飲料中的氨基甲酸乙酯 (urethane) 被認為是可能致肺癌物質，亦常用於誘發小鼠肺癌進行相關研究。即使目前肺癌的診斷與治療方式大有進步，治療後患者五年內的存活率仍低於15%，表明肺癌化學預防與治療策略的研究仍是非常重要的。目前，脂質筏 (lipid raft) 已被證實是細胞膜上的訊息轉運平台，其中的一種重要蛋白質- Flotillin-1 (Flot-1) 被認為是啟動信號傳遞的關鍵點，已有文獻指出Flot-1蛋白不僅在細胞增殖、細胞凋亡、細胞侵襲等作用中扮演關鍵角色，亦會參與癌細胞的發育與進展，臨床數據指出Flot-1蛋白的多寡與包括肺癌在內的癌症嚴重程度呈正相關，因而使其成為有吸引力的抗癌靶標。許多植物提取物通常是新藥的重要來源，近年來從植物中分離出的映貝殼杉烷型二萜類化合物 (ent-Kaurane diterpenoid, EKD) 已被證明具有廣泛的藥理和生理作用，例如抗炎和細胞毒殺活性。因此，我們的研究目的是通過體外和體內試驗評估從越南巴豆 (C.tonkinensis Gagnep) 中分離出的EKD純化物之抗癌作用和使用安全性，同時探討藉由抑制Flot-1表現介導下游細胞存活的訊息傳遞路徑，並誘導細胞凋亡 (apoptosis)、壞死性細胞凋亡 (necroptosis) 和鐵調控的細胞死亡 (ferroptosis) 的機制，是否為EKD對肺癌細胞產生毒殺作用的機轉。
在細胞實驗中，分別使用A549 (〖p53〗^(+/+)) 與H1299 (〖p53〗^(-/-)) 兩種NSCLC細胞株進行治療功效以及相關作用機制的探討。在EKD處理24小時以後，分別利用MTT、trypan blue assay、流式細胞儀、western blot等實驗進行細胞存活率、Flot-1介導的訊息傳遞路徑以及不同細胞死亡途徑活化的觀察，包括細胞凋亡、壞死性細胞凋亡以及鐵調控的細胞死亡。在動物實驗中，EKD的抗癌功效是利用urethane (600 mg / kg) 誘導的肺癌小鼠模型進行10週誘導後，每週三次口服管餵 50 mg / kg bw EKD持續一個月。收集血清、肺、肝及腎組織，分別利用生化分析觀測生理變化與蘇木紫-伊紅染色 (hematoxylin and eosin stain, H＆E stain) 觀察組織形態的改變。安全性評估則依照OECD 407的測試規範，利用ICR小鼠進行28天亞急性口服毒性測試，收集血清、心、肺、肝和腎組織進行後續分析。
在體外試驗結果中，細胞經EKD處理後存活率呈現劑量依賴性地降低並同時誘導細胞凋亡。就分子機制而言，EKD可以降低Flot-1的表達以影響脂質筏的穩定，進而抑制脂質筏所介導的下游細胞存活訊息傳遞，並誘導多種細胞死亡機制，例如細胞凋亡、壞死性細胞凋亡和鐵調控的細胞死亡，進而達到抑癌的功效。在動物功效性評估中，相較於單獨誘發組，經50 mg/kg-bw EKD治療的組別腫瘤體積與數量略有減少，肺腫瘤負荷量相對於控制組的顯著差異性也較單獨誘發組有所回復，同時也減緩肝、腎發炎的現象。在亞急毒性試驗的結果顯示，除最高劑量100 mg/kg-bw EKD組別的器官組織觀察到輕微受損外，50 mg/kg-bw與10 mg/kg-bw的組別均未發現明顯的器官損傷。藉由上述結果證實EKD在50 mg/kg-bw的劑量下可作為肺癌化學預防治療的潛在藥物。此外，由Flot-1抑制Akt及STAT3蛋白所介導的訊息傳遞路徑以及細胞凋亡、壞死性細胞凋亡以及鐵調控的細胞死亡的活化可以被視為EKD治療NSCLC的新型治療策略。

In 2018, WHO has reported lung cancer as the first cancer death worldwide. Although new advancement has been made in lung cancer diagnosis or therapy, the 5-year survival rate is still less than 15%. Therefore, studies on the development of novel chemoprevention and therapeutic strategies for lung cancer remain urgent. At present, lots of plant extracts with the potential to induce cell death and reduce inflammation have been highly suggested as anti-cancer drugs because of their low toxicity and high availability. Thus, my study firstly evaluates the anti-cancer property and the safety of ent-kaurane diterpenoid (EKD) extracted from C. tonkinensis Gagnep by in vitro and in vivo studies. The therapeutic effects and relative mechanisms of EKD are investigated by in vivo and in vitro model. The results indicated that EKD treatment presented a dose-dependently reduce cell viability and simultaneously induce apoptosis, ferroptosis and necroptosis. Furthermore, EKD could reduce the expression of Flotillin-1 and destruct the stability of lipid raft which leads to the inhibition of survival signaling pathways. In the animal experiments, safety assessment is tested by sub-acute oral toxicity in ICR mice according to OECD 407. The efficacy assessment is investigated using urethane-induced lung cancer mouse model with oral gavage of 50 mg/kg EKD. In the sub-acute study, none of the significant damage occurred in histopathology and physiology except the treatment of 100 mg/kg EKD. The efficacy result indicated that EKD could reduce nodule number and diagram compared to urethane treated groups. Taken together, my results indicated that EKD could be a potential agent for lung cancer therapy because of its significant cytotoxicity effects by inducing apoptosis, necroptosis and ferroptosis in cells and the effect to reduce nodule number and diagram in animals. Moreover, the downregulation of Flotillin-1 leading to the inhibition of cell proliferation, also activation of apoptosis, necroptosis and ferroptosis could serve as a new therapeutic target for NSCLC.

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