MAP 激酶在无环核苷膦酸细胞毒性中的作用。

Involvement of MAP kinases in the cytotoxicity of acyclic nucleoside phosphonates.

机构信息

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague 6, Czech Republic.

出版信息

Anticancer Res. 2012 Feb;32(2):497-501.

PMID:22287737

Abstract

BACKGROUND

9-[2-(phosphonomethoxy)ethyl] guanine (PMEG) is a nucleotide analogue with anticancer activity. Here we investigate the role of ERK, p38, JNK and AKT kinases in PMEG-induced apoptosis.

MATERIALS AND METHODS

CCRF-CEM and HL-60 leukemia cells were used to assess MAPK mRNA and protein expression in PMEG-treated cells. MAPK activation was measured using phospho-specific antibodies. Apoptosis was evaluated by caspase-3 and PARP cleavage.

RESULTS

Up-regulation of p38β, γ and δ mRNA were observed following PMEG treatment of CCRF-CEM cells, however, the total protein expression remained unchanged. Neither PMEG nor its analogue 9-[2-(phosphonomethoxy) ethyl]-2,6-diaminopurine (PMEDAP) induced p38 kinase phosphorylation in CCRF-CEM cells, whereas increased p38 phosphorylation was observed in HL-60 cells. The ERK pathway was also activated by these compounds. Pretreatment of the cells with the p38 inhibitor SB203580 diminished drug-induced apoptosis whereas inhibition of ERK, JNK or AKT pathways did not. [corrected].

CONCLUSION

PMEG- and PMEDAP-induced. [corrected].

摘要

背景

9-[2-(膦酸甲氧基)乙基]鸟嘌呤（PMEG）是一种具有抗癌活性的核苷酸类似物。在这里，我们研究了 ERK、p38、JNK 和 AKT 激酶在 PMEG 诱导的细胞凋亡中的作用。

材料与方法

使用 CCRF-CEM 和 HL-60 白血病细胞来评估 PMEG 处理细胞中的 MAPK mRNA 和蛋白表达。使用磷酸化特异性抗体测量 MAPK 激活。通过 caspase-3 和 PARP 切割评估细胞凋亡。

结果

在 CCRF-CEM 细胞中用 PMEG 处理后观察到 p38β、γ 和 δ mRNA 的上调，但总蛋白表达保持不变。PMEG 及其类似物 9-[2-(膦酸甲氧基)乙基]-2,6-二氨基嘌呤（PMEDAP）均未诱导 CCRF-CEM 细胞中 p38 激酶磷酸化，而在 HL-60 细胞中观察到 p38 磷酸化增加。这些化合物还激活了 ERK 通路。用 p38 抑制剂 SB203580 预处理细胞可减少药物诱导的细胞凋亡，而抑制 ERK、JNK 或 AKT 通路则没有。