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  • 學位論文

研究傳統中草藥爵床治療結腸直腸癌的效果

Autophagic effect of traditional Chinese medicine Justicia procumbens on human colorectal cancer HT-29 cells

指導教授 : 蘇純立

摘要


結腸直腸癌不論在全世界或台灣都是主要的死亡原因之一。而現今治療結腸直腸癌的藥物及化學治療易造成病人身體不適,使得病患生活品質低落,造成護理人員在照護病人時的困難。爵床素A是由爵床(Justicia procumbens)萃取出的純化物,使用於傳統中藥,具有消炎、鎮痛、及治療癌症效果。近年的研究結果發現爵床素A會增加大腸結腸癌HT-29和HCT-116細胞內Ku70表現,進而活化caspases表現,導致產生細胞凋亡。也會使NOD-SCID老鼠體內的HT-29細胞的腫瘤生長受到抑制。最近的研究結果也發現細胞凋亡和細胞自噬(Autophagy)存在著相互抑制或促進的關係,因此本研究進一步探討爵床素A是否會引發HT-29細胞產生細胞自噬,以及細胞自噬與細胞凋亡之間的關係。將爵床素A處理HT-29細胞不同時間與不同劑量後以西方墨點法、acridine orange染色與流式細胞儀、共軛焦顯微鏡觀察,實驗結果發現HT-29細胞給予0.5 ?嵱爵床素A處理3~6小時,細胞自噬的指標分子LC3-II的表現增加。進一步探討爵床素A處理的HT-29細胞是經由何種細胞內訊息途徑,西方墨點法實驗發現p-AKT、p- mTOR、p-p70S6k表現受到抑制,Type III PI3K、beclin 1表現增加,證實經爵床素A處理的HT-29細胞是經由抑制AKT/mTOR及促進Type III PI3K/beclin 1細胞內訊息路徑引導產生細胞自噬。然而實驗也發現Type I p-PI3K and p-PDK1不是路徑的上游分子。使用annexin V-FITC和PI雙染觀察經由爵床素A處理的HT-29細胞,並利用流式細胞儀檢測細胞凋亡及細胞自噬的關係,結果證實爵床素A引發細胞自噬的時間早於細胞凋亡的時間。實驗進一步將細胞以自噬抑制劑3-MA處理後再經爵床素A處理HT-29,由西方墨點法、共軛焦顯微鏡及流式細胞儀偵測,發現該細胞自噬受到抑制後,細胞凋亡的比例明顯下降,所以經爵床素A處理的HT-29細胞產生細胞自噬會促進細胞凋亡的產生。本研究期望能找尋具專一性的抗癌藥物以提供癌症病患的不同選擇,促進醫療與護理品質提升。

並列摘要


Colorectal cancer is one of the leading causes of malignant death in western countries as well as in Taiwan. Nowadays, medicines and chemotherapy made patients indisposed. The quality of life is low, that made nursing more difficult. Justicidin A is a pure compound isolated from Justicia procumbens, a traditional herbal remedy for treatment of fever, pain, and cancer in Taiwan. Recent reports have demonstrated that justicidin A induced apoptosis in human colorectal cancer HT-29 and HCT 116 cells and suppressed the growth of HT-29 cells transplanted into NOD-SCID mice. In this study, we observed that justicidin A not only increased the expression of autophagic marker LC3-II by immunoblotting and confocol microscopy, but also augmented the formation of acidic vesicular organelles at 3~6 h by flow cytometry. In addition, the expression of p-AKT, p- mTOR, p-p70S6k were inhibited in justicidin A-treated HT-29 cells demonstrated by western blotting. However, the expression of Type III PI3K and beclin 1 were increased in the cells demonstrated by western blotting. These results suggest that justicidin A-induced autophagic signaling pathways were via inhibition of AKT/mTOR signaling pathway and induction of Type III PI3K/beclin 1 signaling pathway. Annexin V-FITC and PI double staining followed by flow cytometry further revealed that induction of early apoptosis was displayed at 12 h, that was later than the induction of autophagy. Administration of autophagy inhibitor 3-MA further demonstrated that autophagy promoted apoptosis in justicidin A-treated HT-29 cells since 3-MA inhibited the percentage of early apoptotic cells determined by flow cytometry. Taken together, induction of autophagy leading to apoptotic death of the cells suggests chemotherapeutic potential of justicidin A on human colorectal cancer. The purpose of the present study was to discover a drug with selective to enhance quality of nursing.

並列關鍵字

colorectal cancer justicidin A autophagy

參考文獻


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