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研究生:連宜珍
研究生(外文):Yi-Chen Lien
論文名稱:NAD(P)H:QuinoneOxidoreductase(NQO1)的活性參與Beta-Lapachone對人類前列腺癌細胞株(DU145)凋亡之機轉
論文名稱(外文):Involvement of NAD(P)H:Quinone Oxidoreductase (NQO1) Activity in the Mechanism of Beta-Lapachone–Mediated Apoptosis on Human Prostate Cancer (DU145)Cells
指導教授:周逸鵬
指導教授(外文):Yat-Pang Chau
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:解剖暨細胞生物學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:86
中文關鍵詞:人類前列腺癌細胞株細胞凋亡
外文關鍵詞:NAD(P)H:Quinone Oxidoreductase (NQO1)beta-Lapachoneapoptosishuman prostate cancer cell line
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beta-Lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol(1,2-b)pyran-5,6-dione)是一種醌類抗癌藥物,在過去文獻中指出beta-lapachone對多種癌細胞具有強力的毒殺作用,但它的毒殺機制卻至今尚未完全瞭解。本實驗主要目的在探討beta-lapachone對人類前列腺癌細胞株DU145的毒殺機制。實驗結果顯示:經beta-lapachone處理後會造成細胞內鈣離子濃度失衡、caspase-7、caspase-12和calpain的切割以及MAP Kinases的活化,共同投予caspase抑制劑(z-VAD-FMK)或calpain抑制劑(ALLM 、ALLN )卻無法降低細胞死亡的比例,由此可見;caspases和calpains在beta-lapachone引發DU145細胞凋亡之早期過程中並未扮演著重要的角色。過去有研究報告記載NQO1這種特殊的氧化還原酶與不同的醌類抗癌藥物之間會有不同反應發生。在本實驗中我們發現共同處理NQO1抑制劑(dicoumarol)後,beta-lapachone對人類前列腺癌細胞株DU145的毒性大幅減少,細胞內鈣離子濃度也維持在正常的情形。利用細胞內鈣離子螯和劑BAPTA-AM降低beta-lapachone處理後細胞內鈣離子增加的趨勢,可使細胞死亡情形趨緩。而且經dicoumarol或BAPTA-AM處理後則可以減少beta-lapachone處理後細胞內caspase-7、 caspase-12和calpain的切割以及MAP Kinases的活化。根據上述的實驗結果我們認為□-lapachone的毒性主要是利用NQO1的活性,造成細胞內鈣離子濃度失衡,進而活化caspase-7、 caspase-12和calpain以及MAP Kinases (p38, ERK, JNK)的磷酸化訊息,導致DU145細胞凋亡。
Prostate cancer is the most commonly diagnosed neoplasm in western countries. However, this type of cancer is resistant to chemotherapy. Identification of anticancer chemicals against prostate cancer may be an important event for medicine. beta-Lapachone (3,4,dihydro-2,2-dimethyl -2H-naphtho- [1,2-b]pyran-5,6- dione), a natural product extracted from the lapacho tree (Tabebuia avellanedae), has been shown to have anticancer and antiviral effects. We here reported that beta-lapachone can induce the human prostate cancer cell undergoing apoptosis. beta-Lapachone-induced apoptosis has been characterized by annexin-V labeling. Our results also showed that pretreatment with general caspase inhibitor, z-VAD-FMK, and calpain inhibitors including ALLM or ALLN, failed to prevent apoptotic cell death induced by beta-lapachone.Moreover, treatment of beta-lapachone triggered calcium efflux and the phosphorylation of ERK p38 and JNK. Addition of NQO1 inhibitor, dicoumarol, or intracellular calcium chelator, BAPTA, provided significant protection against apoptosis by preventing calcium efflux, and inhibiting the activation of caspases and calpains, respectively. More, addition of dicoumarol, or BAPTA blocked the phosphorylation of ERK p38 and JNK in beta-lapachone-treated cells. Taken together, we suggest that beta-lapachone exerts its cytotoxicity through the NQO1 activity that leads to calcium unbalance, and subsequently stimulates the activation of MAP kinases and the cleavages of caspases and calpains.
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結果. 15-17.
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