抗癌藥物Sunitinib對人類血癌細胞分化作用之分子機轉研究

The Molecular Mechanisms of Sunitinib-induced Cell Differentiation in Human Acute Myeloid Leukemia Cells

陳銘洲(Ming-Chou Chen)

指導教授 ： 余長澤

共同指導教授 ： 徐士蘭

國立暨南國際大學/科技學院/生物醫學科技研究所/碩士(2010年)

https://doi.org/10.6837/NCNU.2010.00185

摘要

在臨床上，化學治療和骨髓移植為主要治療急性骨髓性白血病之方法。在正常狀態下，細胞分化是生物個體正常生長與動態平衡不可缺少的作用。誘導血癌細胞分化，是一種有效治療急性白血病的方法。Sunitinib，是一種口服藥物，為多標靶酪胺酸激酶接受體的抑製劑，無論在體外或體內，都能有效的誘導急性骨髓性白血病的細胞生長停滯和細胞凋亡。使用Sunitinib和維他命D3，已經被證實能有效的誘導急性骨髓性白血病細胞之分化，本論文之研究，在探討Sunitinib對於人類血癌細胞（HL-60及KG-1）生長存活之影響，且主要針對其對細胞分化作用機制之探討。以體外培養的兩株人類血癌細胞（HL-60及KG-1），處理Sunitinib兩天後，由細胞生長曲線及流式細胞儀分析的結果，發現Sunitinib能抑制細胞生長。由染色結果發現細胞已轉變為分化細胞之型態。分析細胞膜表面的分化分子CD14與CD11b的表現，發現處理Sunitinib可增加細胞表面CD14及CD11b之表現。進而一步探討可調控CD14的分子PKCα及C/EBPβ之表現也隨之而增加，且PKC下游分子HOXA9的表現會減少，利用PKC抑制劑Go6976處理細胞，可使得Sunitinib誘導的CD14與CD11b細胞表面特異分子之表現量下降。本論文之結果顯示，處理Sunitinib會使血癌細胞HL-60經由PKCα及C/EBPβ的路徑調控細胞分化之分子，使細胞膜表面特異性分子CD14與CD11b的表現增加，細胞走向分化的途徑。

關鍵字

急性骨髓性白血病 ； 紓癌特 ； 酪胺酸激酶接受體 ； 細胞分化 ； 細胞膜表面特異性分子

並列摘要

Chemotherapy and Bone marrow transplantation are the major treatments for acute myeloid leukemia (AML). Cell differentiation is essential for normal growth and homeostasis. Inducing myelopoiesis can potentially serve as differentiation therapy for myeloid leukemia. Sunitinib, an orally available multitargeted receptor tyrosine kinases inhibitor, effectively induced growth arrest and apoptosis of acute myelogenous leukemia (AML) cells both in vitro and in vivo. Sunitinib has been shown to potentiate VitD3-induced AML differentiation. In this study, human AML cell lines, HL-60 and KG-1, were used to address the effect of sunitinib alone on differentiation of AML. Treatment of HL-60 and KG-1 cells with sunitinib resulted in a dose-dependent growth inhibition. Data from morphological investigation and flow cytometry showed that sunitinib could induce monocyte-like differentiation in both HL-60 and KG-1 cells. Treatment with sunitinib for 2 days drastically increased the levels of monocyte differentiation markers, including CD14, CD11b, CD68, and myeloperoxidase. This event was accompanied by the increase of C/EBPβ and PKCα expression, as well as decrease of C/EBPα and HOXA9 expression. Incubation with a PKC inhibitor Go6976 significantly suppressed sunitinib-induced AML cell differentiation. Our findings suggest that sunitinib-induced AML cell differentiation might be via a PKC activation signaling pathway.

並列關鍵字

Acute myeloid leukemia(AML) ； Sunitinib ； Receptor tyrosine kinases ； Cell differentiation ； Monocyte differentiation markers

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