Characterization of cells resistant to the potent histone deacetylase inhibitor spiruchostatin B (SP-B) and effect of overexpressed p21waf1/cip1 on the SP-B resistance or susceptibility of human leukemia cells.
Characterization of cells resistant to the potent histone deacetylase inhibitor spiruchostatin B (SP-B) and effect of overexpressed p21waf1/cip1 on the SP-B resistance or susceptibility of human leukemia cells.
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DOI：
10.3892/ijo.2012.1507
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发表时间：
2012-09
影响因子：
5.2
通讯作者：
Ishikawa M
中科院分区：
文献类型：
--
作者：
Kanno S;Maeda N;Tomizawa A;Yomogida S;Katoh T;Ishikawa M
我们之前发现，在许多白血病细胞系中，B细胞白血病细胞系NALM-6对有效的组蛋白去乙酰化酶（HDAC）抑制剂spiruchostatin B （SP-B）具有最高的易感性。我们还发现sp - b诱导的细胞毒性依赖于p21waf1/cip1表达介导的细胞凋亡诱导。在本研究中，我们从低SP-B浓度开始，通过持续暴露于SP-B，产生并表征了一个稳定的，抗SP-B的NALM-6细胞系（NALM-6/SP-B）。NALM-6/SP-B细胞对FK228（与SP-B具有相似的化学结构）的抗性也更高，对P-gp底物阿霉素和新碱的抗性略高于亲本细胞，但对其他HDAC抑制剂和紫杉醇的敏感性与亲本细胞相似。NALM-6/SP-B细胞中HDAC1、p53、Bax、Bcl-2、Fas、caspase-3、c-Myc和MDR1 mRNA的基础表达量与亲本细胞相比变化不大，但p21waf1/cip1 mRNA表达量下降。引入外源性p21waf1/cip1表达载体恢复SP-B诱导NALM-6/SP-B细胞凋亡。此外，p21waf1/cip1过表达增强了SP-B对人红细胞白血病细胞株K562的诱导凋亡作用，而K562对SP-B的敏感性低于NALM-6细胞。这些结果表明，作为NALM-6/SP-B细胞的一个特征，p21waf1/cip1的下调对它们对SP-B的抗性很重要，并且可以通过引入外源p21waf1/cip1来克服这种SP-B抗性。此外，将p21waf1/cip1引入其他白血病细胞（如K562）可能会增强它们对SP-B的易感性。这是首次报道SP-B耐药细胞的特性，以及过表达p21waf1/cip1对人白血病细胞对SP-B的耐药或易感性的影响。
We previously showed that the B cell leukemia cell line NALM-6 had the highest susceptibility among a number of leukemia cell lines to spiruchostatin B (SP-B), a potent histone deacetylase (HDAC) inhibitor. We also showed that SP-B-induced cytotoxicity depended on induction of apoptosis that was mediated by p21waf1/cip1 expression. In the present study, we generated and characterized a stable, SP-B-resistant NALM-6 cell line (NALM-6/SP-B) by continuous exposure to SP-B, starting with a low SP-B concentration. NALM-6/SP-B cells were also more resistant to FK228, which has a similar chemical structure to SP-B, and were slightly more resistant to the P-gp substrates doxorubicin and vincristine than parental cells, but displayed similar susceptibility to other HDAC inhibitors and to paclitaxel as the parental cells. There was little change in the basal mRNA expression of HDAC1, p53, Bax, Bcl-2, Fas, caspase-3, c-Myc and MDR1 in NALM-6/SP-B compared to parental cells, but the mRNA expression of p21waf1/cip1 was decreased. The introduction of an exogenous p21waf1/cip1 expression vector restored SP-B induction of NALM-6/SP-B cell apoptosis. Moreover, overexpressed p21waf1/cip1 enhanced SP-B induction of the apoptosis of the human erythroleukemia leukemia cell line K562 which is less susceptible to SP-B than NALM-6 cells. These results suggest that downregulation of p21waf1/cip1, which is a characteristic feature of NALM-6/SP-B cells, was important for their resistance to SP-B, and that this SP-B resistance could be overcome by the introduction of exogenous p21waf1/cip1. Furthermore, introduction of p21waf1/cip1 to other leukemia cells such as K562 may enhance their susceptibility to SP-B. This is the first report of the characterization of SP-B-resistant cells and of the effect of overexpressed p21waf1/cip1 on the resistance or susceptibility of human leukemia cells to SP-B.
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DOI：
10.1124/jpet.105.083956
发表时间：
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影响因子：
3.5
作者：
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通讯作者：
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