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織蛋白去乙醯化酶 ; 抑制劑 ( 丙基戊酸 ) 對急性白血病細胞生長、凋亡和 分化特性的研究

論文名稱:織蛋白去乙醯化酶抑制劑 ( 丙基戊酸 ) 對急性白血病細胞生長、凋亡和分化特性的研究



畢業時間: 93 學年度第 1 學期

指導教授:劉興璟 助理教授 醫學研究所

林建煌 教授 醫學研究所

Epigenetic 調控基因表現,對造血作用與白血病的形成有密切關聯。組織蛋白去乙醯化酶是 epigenet ic 調控的重要成員之一。本研究在探討組織蛋白去乙醯化酶與白血病的增生、細胞分化、細胞凋亡 的關係。發現組織蛋白去乙醯化酶抑制劑 ( 酪酸鈉、酪酸苯丙基戊酸和 SAHA) ,能有效的抑制人 類急性骨髓性白血病細胞株的增生,誘導細胞分化或是促進細胞凋亡作用,酪酸鈉、酪酸苯和 SA HA 使細胞週期停滯 G0/G1 期,而丙基戊酸不影響細胞週期。同時發現組織蛋白去乙醯化酶抑制劑

,能誘導人類急性骨髓性白血病細胞株走向單核球分化,酪酸鈉能有效誘導 CD11c 表現,丙基戊 酸對誘導 CD13 表現最好,而四種藥劑都能有效誘導 CD14 表現,並增加 α-Naphthyl Acetate Esteras e (NAE) 陽性細胞,但 NBT (nitroblue tetrazolium) 還原反應細胞很微量。因此我們針對丙基戊酸,

治療人類急性骨髓性白血病單核球細胞株 (THP-1) 的影響,研究發現經由細胞週期蛋白質表現,

丙基戊酸誘導 cyclin D1 、 P21 和 P27 表現, cyclin D1 和 P21 誘導骨髓性細胞走向分化。而細 胞走向分化可能跟核酸 c-Jun 和蛋白質表現有關,及 Bcl-2 、 bid 、 caspase-9 和 caspase-3 蛋白 質表現,誘導骨髓性細胞凋亡作用。凋亡路徑可能是啟動死亡接受器 (death receptor) 與粒線體路 徑,而經由 tBid 使兩者路徑有交互聯結,而丙基戊酸活化 JNK 路徑對誘導骨髓性細胞分化作用



Characterization of the Histone Deacetylase Inhibitor (Valproic Acid) on the Growth, Apoptosis and Differentiation of Acute

Myeloid Leukemia

Epigenetic control of gene expression plays an important role in hematopoiesis and leukemoge

nesis. One of the major components in epigenetic regulation of gene expression is histone acet

ylation.Recent studies have shown that histone deacetylase inhibitors (HDACIs) might be usef

ul for treating hematopoietic malignancies. However the effects of these HDACIs on human a

cute myeloid leukemia (AML) have not been studied comprehensively. In this study, we exam

ined the effects of several clinically available HDACIs on the proliferation, differentiation and

apoptosis of AML in vitro. First HL-60 cells were treated with increasing concentrations of so

dium butyrate (SB), a prototypic HDACI, phenylbutyrate (PB), and suberoylanilide hydroxam

ic acid (SAHA), an HDACI in phase-I clinical trials, valproic acid (VA) , a clinically available

agent for neurological disorders.We found that SB, PB, and SAHA were able to arrest cell cyc

le at G0/G1 phase, but VA did not. SB and VA significantly induced the expression of CD11c

and CD13, respectively. CD14 expression was upregulated by all four agents, All four agents i

nduced mild neutrophilic and marked monocytic differentiation evidenced by nitroblue tetrazo

lium (NBT) tests andα-Naphthyl Acetate Esterase (NAE) staining,respectively. Further elucida

tion of VA induced apoptosis through both mitochondrial and death receptor pathway.VA ind

uced cyclin D1, p21 and p27 expression, cycle D1 and p21 might relate cell differentiation,so

cell cycle did not arrest at G0/G1 phase in 48H.Valproic acid activated JNK pathway might pl

ay an important role in monocytic differentiation.


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