- 學位論文
探討Deferasirox對急性淋巴性白血病的細胞毒殺效應
The cytotoxic effects of Deferasirox on acute lymphoblastic leukemia
摘要
急性淋巴性白血病（Acute lymphoblastic leukemia, 以下簡稱ALL）是兒童癌症中盛行率最高的疾病，ALL依癌化的細胞不同，可粗分為T cell ALL (T-ALL)及B cell ALL (B-ALL)。大體而言，兒童ALL的存活率可達8至9成，然而，BCR-ABL1的B-ALL (存活率約4到5成)及T-ALL (存活率約6到7成)是兩個著名的例外。如何增進這兩族群的存活率是兒癌症治療中重要的議題。Deferasirox (DFX)為口服鐵螯合劑。除了鐵螯合劑的功能之外，於細胞實驗及動物實驗中發現，DFX能抑制許多癌症細胞的生長。NRF2全名是nuclear factor, erythroid 2 like 2，是調節增強細胞抗氧化能力的transcription factor。在平時，NRF2的表現可增加細胞抗氧化的防禦力、抑制癌化；然而，在已癌化的細胞內，NRF2的表現反而會促進細胞增生及存活、增加對化療藥和胞內過氧化物的抗性。迄今，尚無人探討DFX對ALL cell line生長的影響及其與NRF2表現的關聯。我們使用T-ALL 及 B-ALLBCR-ABL1(+) 兩株cell line，在培養皿中加入不同濃度的DFX，經過不同作用時間後，探討細胞的viability, apoptosis程度,過氧化物（Reactive oxygen species, ROS）產量及NRF2表現量的變化。經過實驗證明，DFX可抑制T-ALL 及 B-ALLBCR-ABL1(+)cell line的生長、促進細胞凋亡。實驗也發現，ROS產量於給藥後是增加的，NRF2的表現量於最初的四小時內短暫上升，之後下降。推測ROS產量的增加與ALL細胞凋亡有關，而NRF2表現量的下降與細胞死亡間是否有關聯，須待後續進一步的實驗判定。
並列摘要
Acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy. ALL comprises B-lineage (B-ALL), T-lineage (T-ALL), and uncommon variants. The overall survival rate of childhood ALL can be up to 80~90% under modern treatment. However, B-ALL with BCR- ABL1 translocation and T-ALL confer ominous prognosis. How to improve the survival rate of these subtypes is an important issue in pediatric leukemia treatment. Deferasirox (DFX) is an oral iron chelator. Beside to be an iron chelator, DFX was found capable to suppress tumor cell proliferation in many cell-line/animal studies. NRF2[nuclear factor, erythroid 2 like 2 (NFE2L2)] is a transcription factor that can enhance anti-oxidative ability of cells. Under normal circumstance, increasing NRF2 expression can strengthen cellular defense to external stress, prevent tumorigenesis and progression. On the contrary, increasing NRF2 expression in cancer cells can 1). fortify cellular defense against high endogenous levels of reactive oxygen species(ROS), 2). increas cancer cell survival, 3). enhance resistance to chemotherapy and 4). promote metabolic reprogramm to enhance cell proliferation. Todate, there is no discussion about DFX’s effect on ALL cells and its association with NRF2. We use two different cell lines (T-ALL and B-ALLBCR-ABL1(+)) for experiments. Different concentrations of DFX were added to cell-culture dishes/plates. After different acting time, we analyzed viability, apoptosis extent, ROS amount and the expression level of NRF2 of the cells. The expirement result showed that DFX could significantly suppress ALL cell-line growth. ROS production increase after DFX treatment. The NRF2 expression level is transiently up-regulated in first 4 hrs and decreased later. This is the first study demonstrating that DFX can suppress human ALL cells growth. One possbile means is through the increasing ROS amount. Whether the depressed NRF2 expression level plays a role in ALL cell dying process needs further explore.