The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells.
The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells.
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DOI：
10.1038/leu.2011.67
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发表时间：
2011-07
期刊：
影响因子：
11.4
通讯作者：
Holyoake, T. L.
中科院分区：
文献类型：
--
作者：
Pellicano, F.;Simara, P.;Sinclair, A.;Helgason, G. V.;Copland, M.;Grant, S.;Holyoake, T. L.
细胞毒性法尼基转移酶抑制剂BMS-214662已被证明可有效诱导原始CD 34+慢性髓性白血病（CML）干/祖细胞中的线粒体凋亡。在这里，为了增强BMS-214662的凋亡作用，我们通过用高度选择性ATP非竞争性MEK抑制剂PD 184352处理CD 34 + CML干/祖细胞，进一步靶向BCR-ABL下游的RAS-MEK-ERK通路。PD 184352增加了BMS-214662在CML急变细胞系K562和原代慢性期CD 34 + CML细胞中的凋亡效应。与BMS-214662相比，联合治疗后，我们观察到ERK磷酸化抑制，Annexin-V水平增加，半胱天冬酶-3，8和9活化和线粒体损伤增强，与抗凋亡BCL-2家族蛋白MCL-1水平降低相关。显性失活突变体对K-RAS功能的抑制导致CML细胞死亡，添加BMS-214662和PD 184352进一步增强了该过程。总之，这些发现表明，添加MEK抑制剂提高了BMS-214662选择性靶向CML干细胞/祖细胞的能力，CML干细胞/祖细胞对酪氨酸激酶抑制剂治疗不敏感，被认为是导致疾病持续和复发的原因。
The cytotoxic farnesyl transferase inhibitor BMS-214662 has been shown to potently induce mitochondrial apoptosis in primitive CD34+ chronic myeloid leukaemia (CML) stem/progenitor cells. Here, to enhance the BMS-214662 apoptotic effect, we further targeted the RAS-MEK-ERK pathway, downstream of BCR-ABL, by treating CD34+ CML stem/progenitor cells with a highly selective ATP non-competitive MEK inhibitor, PD184352. PD184352 increased the apoptotic effect of BMS-214662 in a CML blast crisis cell line, K562, and in primary chronic phase CD34+ CML cells. Compared to BMS-214662, after combination treatment we observed inhibition of ERK phosphorylation, increased Annexin-V levels, caspase-3, 8 and 9 activation and potentiated mitochondrial damage, associated with decreased levels of anti-apoptotic BCL-2 family protein MCL-1. Inhibition of K-RAS function by a dominant negative mutant resulted in CML cell death and this process was further enhanced by the addition of BMS-214662 and PD184352. Together, these findings suggest that the addition of a MEK inhibitor improves the ability of BMS-214662 to selectively target CML stem/progenitor cells, notoriously insensitive to tyrosine kinase inhibitor treatment and presumed to be responsible for the persistence and relapse of the disease.
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影响因子：
50.3
作者：
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