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標題: | 局部麻醉藥劑促進腫瘤細胞凋亡之研究 Apoptosis Induced by Local Anesthetics in Tumor Cells |
作者: | Yuan-Ching Chang 張源清 |
指導教授: | 胡孟君(Meng-Chun Hu) |
關鍵字: | 乳癌,甲狀腺癌,麻醉,局部麻醉劑,細胞凋亡, breast cancer,thyroid cancer,local anesthetics,anesthesia,apoptosis, |
出版年 : | 2014 |
學位: | 博士 |
摘要: | 乳癌對女性健康和精神方面一直是莫大的威脅。佔台灣青壯年(30~60歲)女性癌症發生率第一位。值得注意的是,台灣地區婦女乳癌症發生率有逐年升高的趨勢。另外甲狀腺癌的發生率近年來也有顯著增加。外科手術仍是乳癌、甲狀腺癌治療中之極重要一環。吸入性氣體麻醉全身麻醉在接受手術的病人上可能有術後疼痛及噁心、嘔吐的副作用。手術創傷也會引起不當免疫反應,而免疫缺損則可能促成腫瘤生長和擴散。局部麻醉可以阻止外科手術創傷訊息傳入,已經廣泛應用於癌症診斷切片和細胞抽吸。近來更可使用局部麻醉藥品在鎮靜麻醉下應用於乳癌手術。
本研究使用之局部麻醉藥品(Lidocaine, Bupivacaine) 以乳癌腫瘤、甲狀腺癌細胞和利用腫瘤之動物模式,發現其對腫瘤細胞抑制的效果。 本研究發現局部麻醉藥品以低於臨床乳癌手術使用的局部麻醉劑量,影響粒腺體和胞外凋亡路徑而導致的凋亡蛋白酶7,8,9活化,就會造成乳癌細胞的死亡,而對正常乳腺細胞株較無影響。 另外也發現局部麻醉藥品能抑制甲狀腺癌腫瘤細胞的生存能力,減少細胞群落形成。藉由瓦解粒線體膜電位,釋放细胞色素C (Cytochrome C),活化凋亡蛋白酶3,7,升高Bax/Bcl-2比例進而引發甲狀腺癌細胞凋亡及壞死。由局部麻醉藥品所誘導之MAPK訊息傳遞路徑可能為其促進細胞凋亡之重要機轉。 總結來說,本研究發現局部麻醉劑的抑制癌細胞效果。我們大膽預測,本研究的延伸可能帶來醫界重大的衝擊,提供兼顧腫瘤控制的乳癌和甲狀腺癌手術麻醉模式。 The incidence of breast and thyroid cancer has remarkably increased in recent years. Local anesthetics are frequently used in fine-needle aspiration of thyroid lesions and locoregional control of persistent or recurrent thyroid cancer. Wound infiltration with local anesthetics reduces postoperative pain after breast surgery. Recent evidence suggests that local anesthetics have a broad spectrum of effects including inhibition of cell proliferation and induction of apoptosis in neuronal and other types of cells. In this study, we demonstrated that treatment with lidocaine and bupivacaine resulted in decreased cell viability and colony formation of both 8505C and K1 cells in a dose-dependent manner. Lidocaine and bupivacaine induced apoptosis, and necrosis in high concentrations, as determined by flow cytometry. Lidocaine and bupivacaine caused disruption of mitochondrial membrane potential and release of cytochrome c, accompanied by activation of caspase 3 and 7, PARP cleavage, and induction of a higher ratio of Bax/Bcl-2. Based on microarray and pathway analysis, apoptosis is the prominent transcriptional change common to lidocaine and bupivacaine treatment. Furthermore, lidocaine and bupivacaine attenuated extracellular signal-regulated kinase 1/2 (ERK1/2) activity and induced activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase. Pharmacological inhibitors of MAPK/ERK kinase and p38 MAPK suppressed caspase 3 activation and PARP cleavage. Taken together, our results for the first time demonstrate the cytotoxic effects of local anesthetics on thyroid cancer cells and implicate the MAPK pathways as an important mechanism. We also demonstrated that the apoptotic effects of local anesthetics in human breast tumor cells. Treatment of breast tumor cells with lidocaine and bupivacaine at clinically relevant concentrations resulted in inhibition of cell viability via induction of apoptosis. The effects were more prominent in MCF-7 cells than in MCF-10A cells. Treatment with local anesthetics induced caspase 7, 8, 9, and poly ADP-ribose polymerase (PARP) cleavage. The cleavage of caspase 7 and PARP induced by local anesthetics was effectively blocked by caspase inhibitors. Furthermore, treatment of MCF-7 xenografts with local anesthetics resulted in higher expression of cleaved caspase 7 and an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. Our findings reveal previously unrecognized beneficial actions of local anesthetics and call for further studies to assess the oncologic advantages of their use during breast cancer surgery and in the management of patients with thyroid cancer. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/5352 |
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