Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts
Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts
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DOI：
10.1096/fasebj.13.14.1991
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发表时间：
1999-11-01
期刊：
影响因子：
4.8
通讯作者：
Kofler, R
中科院分区：
文献类型：
--
作者：
Bernhard, D;Ausserlechner, MJ;Kofler, R
组蛋白去乙酰酶抑制剂和潜在的抗癌药物丁酸钠是生长停滞、分化的一般诱导剂，在某些细胞类型中，还可以诱导细胞凋亡。在人CCRF-CEM中，急性T淋巴细胞白血病细胞、丁酸盐和其他组蛋白去乙酰化酶抑制剂导致G2/M细胞周期停滞和细胞凋亡。四环素调控的转基因p16/INK4A基因表达使细胞G0/G1期停滞，保护细胞免受丁酸诱导的细胞死亡，但不影响组蛋白超乙酰化的程度，提示后者可能是诱导细胞死亡的必要因素，但不是充分条件。广谱caspase抑制剂benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone(ZVAD)和四肽效应型caspase抑制剂benzyloxycarbonyl-Asp-Glu-Val-Asp.fluoromethylketone(DEVd)和benzyloxycarbonyl-Val-Glu-Ile-Asp.fluoromethyl-ketone(VEID)可延缓但不能阻止细胞核的凋亡，但不能阻止G2/M期的停滞；Bcl2过表达可部分保护稳定转染的CCRF-CEM亚系免受丁酸诱导的细胞凋亡，但对丁酸诱导的生长抑制无影响，进一步区分了这两种作用。C-myc在CCRF-CEM细胞中的结构性表达被丁酸盐下调，但这不是细胞死亡的原因。相反，四环素诱导的转基因c-myc使稳定转染的CCRF-CEM衍生物敏化丁酸诱导的细胞死亡。-Bernhard，D.，Ausserlechner，M.J.，Tonko，M.，Loffler，M.，Hartmann，B.L.，Csordas，A.，Kofler，R.组蛋白去乙酰化酶抑制剂丁酸钠诱导人白血病淋巴母细胞凋亡。
The histone deacetylase inhibitor and potential anti-cancer drug sodium butyrate is a general inducer of growth arrest, differentiation, and in certain cell types, apoptosis. In human CCRF-CEM, acute T lymphoblastic leukemia cells, butyrate, and other histone deacetylase inhibitors caused G2/M cell cycle arrest as well as apoptotic cell death. Forced G0/G1 arrest by tetracycline-regulated expression of transgenic p16/INK4A protected the cells from butyrate-induced cell death without affecting the extent of histone hyperacetylation, suggesting that the latter may be necessary, but not sufficient, for cell death induction. Nuclear apoptosis, but not G2/M arrest, was delayed but not prevented by the tripeptide broad-range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD) and, to a lesser extent, by the tetrapeptide 'effector caspase' inhibitors benzyloxycarbonyl-Asp-Glu-Val-Asp.fluoromethylketone (DEVD) and benzyloxycarbonyl-Val-Glu-Ile-Asp.fluoromethyl-ketone (VEID); however, the viral protein inhibitor of 'inducer caspases', crmA, had no effect. Bcl-2 overexpression partially protected stably transfected CCRF-CEM sublines from butyrate-induced apoptosis, but showed no effect on butyrate-induced growth inhibition, further distinguishing these two butyrate effects. c-myc, constitutively expressed in CCRF-CEM cells, was down-regulated by butyrate, but this was not causative for cell death. On the contrary, tetracycline-induced transgenic c-myc sensitized stably transfected CCRF-CEM derivatives to butyrate-induced cell death.-Bernhard, D., Ausserlechner, M. J., Tonko, M., Loffler, M., Hartmann, B. L., Csordas, A., Kofler, R. Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts.