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標題: | 分析天然植物對苯二酚衍生物HQ17(3)對帶有t(4;11)染色體轉位急性淋巴性白血病細胞株RS4;11的影響 The Effects of Botanical Alkyl Hydroquinone Derivative HQ17(3) on Acute Lymphoblastic Leukemia Cell Line, RS4;11 Harboring t(4;11) Chromosome Translocation |
作者: | Yi-Wen Kao 高意雯 |
指導教授: | 胡忠怡(Chung-Yi Hu) |
關鍵字: | 急性淋巴性白血病,HQ17(3),細胞凋亡,硫胱胺酸蛋白酶,活性氧族群, acute lymphoblastic leukemia (ALL),HQ17(3),apoptosis,caspase,reactive oxygen species (ROS), |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | 急性淋巴性白血病(Acute lymphoblastic leukemia, ALL)為造血系統不正常病變導致不成熟淋巴球異常增生的疾病;佔兒童癌症發生的第一位。目前兒童ALL的藥物治療成效良好,五年無事件存活率約達76~86%,不過帶有t(9;22)或MLL基因轉位的極高危險群(Very high risk, VHR)病人經密集高劑量化學治療後尚無法達到長時間的緩解。因此,發展對VHR-ALL病患更有效的治療療程或者新藥是ALL的重要研究課題。漆樹萃取物對苯二酚衍生物 HQ17(3)於先前曾經被研究發現有抗癌能力,且低濃度即對惡性骨髓性血癌細胞株HL-60有毒殺效果。
本研究於先驅測試中確定低濃度HQ17(3)對四株ALL細胞株即具有細胞毒性,乃選定帶有MLL-AF4基因轉位的RS4;11細胞株為標的,研究HQ17(3)造成VHR ALL細胞毒性之機轉。結果顯示HQ17(3)會誘導RS4;11細胞株中活性氧(ROS)的產生,破壞粒線體膜電位,硫胱胺酸蛋白酶(Caspase)活化,多二磷酸腺苷核糖聚合酶(PARP)被切割,細胞發生凋亡(Apoptosis)。加入泛硫胱胺酸蛋白酶抑制劑(Pan-caspase inhibnitor)雖然可以抑制HQ17(3)所誘發的caspase活性,但是卻無法抑制PARP切割與細胞死亡。抗氧化劑(Antioxidants, ROS scavengers)榖胱苷肽(GSH)和維生素C可以減緩HQ17(3)所誘導的ROS產生,減少細胞粒線體膜電位的變化,挽救細胞死亡。綜合本研究的實驗結果顯示ROS是HQ17(3)誘導RS4;11細胞死亡的主要原因之一;HQ17(3)雖亦造成caspase活化,但非HQ17(3)誘導RS4;11細胞死亡的原因。此外,本研究結果指出若可選擇性誘導細胞中ROS產生,可能有潛力發展輔助治療如MLL-AF4基因轉位的VHR ALL的策略。 Acute lymphoblastic leukemia (ALL), a haematopoietic malignant disorder of lymphoid cells, is the most prevalent childhood cancer. Although the rate of success in the treatment of childhood ALL has been improved with a 5-year event-free survival of 76-88%, patients succumbing very-high- risk (VHR) ALLs (those harboring t(9;22) or MLL rearrangements chromosomal abnormalities) display poor clinical outcomes even with intensive chemotherapies. Thus, more effective treatment protocols or new drugs are beneficial for these patients. HQ17(3)(10’(Z),13’(E),15’(E)-heptadecatrienyl- hydroquinone), isolated from the sap of Rhus succedanea, had been reported to have anti-cancer activity, and low concentration of HQ17(3) showed cytotoxicity to the HL-60 myeloid leukemia cells. Our pilot screening confirmed HQ17(3) exhibited effective cytotoxic effect on four tested ALL cell lines. Thus, the RS4;11 cell line harboring MLL-AF4 gene translocation was chosen for the detailed investigation of the effects of HQ17(3) on VHR ALL cells. HQ17(3) induced reactive oxygen species (ROS) production in RS4;11 cells, and disrupted the mitochondrial membrane potential, activated caspase-3, and cleaved poly (ADP-ribose) polymerase (PARP). RS4;11 cells treated with HQ17(3) showed features of apoptotic cell death. Pan-caspase inhibitor could effectively inhibit HQ17(3)-induced caspase-3 activation, but could neither reduce HQ17(3)-induced PARP cleavage nor rescue cells from death. Antioxidants or ROS scavengers (GSH, vitamin C) attenuated HQ17(3)-induced ROS production, mitochondrial membrane potential lost, and cell death. These results indicated that oxidative stress associated with ROS production is one of the major mechanisms to cause HQ17(3)-induced RS4;11 cell death. In conclusion, HQ17(3) displayed significant anti-leukemic activity by inducing ROS and cell apoptotic death. These results further indicated that ROS-inducing agents might potentially augment the treatment for VHR ALL with t(4;11) translocation. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37629 |
全文授權: | 有償授權 |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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