Blockade of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase and murine double minute synergistically induces Apoptosis in acute myeloid leukemia via BH3-only proteins Puma and Bim.
Blockade of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase and murine double minute synergistically induces Apoptosis in acute myeloid leukemia via BH3-only proteins Puma and Bim.
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DOI：
10.1158/0008-5472.can-09-0878
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发表时间：
2010-03-15
期刊：
影响因子：
11.2
通讯作者：
Andreeff M
中科院分区：
文献类型：
--
作者：
Zhang W;Konopleva M;Burks JK;Dywer KC;Schober WD;Yang JY;McQueen TJ;Hung MC;Andreeff M
Ras/Raf/MEK/ERK和/或MDM 2/p53信号通路的分子畸变在80%和50%的原发性AML样本中报告，结果较差。在这项研究中，研究了AZD 6244联合MEK抑制和MDM 2拮抗剂Nutlin 3a非遗传毒性p53激活的抗白血病作用。AZD 6244和Nutlin 3a同时阻断MEK和MDM 2信号传导在AML细胞系（OCI/AML 3和MOLM 13细胞中CI分别为0.06 ± 0.03和0.43 ± 0.03）和原代AML细胞（CI = 0.52 ± 0.01）中引发协同促凋亡反应。从机制上讲，该组合上调了仅BH 3蛋白Puma和Bim的水平，部分是通过FOXO 3a转录因子的转录上调。通过短干扰RNA抑制Puma和Bim拯救OCI/AML 3细胞免于AZD/Nutlin诱导的凋亡。这些结果强烈地表明组合的MEK/MDM 2阻断在AML中的治疗潜力，并暗示Puma和Bim是AML细胞存活的主要调节剂。
Molecular aberrations of the Ras/Raf/MEK/ERK and/or MDM2/p53 signaling pathways have been reported in 80% and 50% of primary AML samples and confer poor outcome. In this study, anti-leukemic effects of combined MEK inhibition by AZD6244 and non-genotoxic p53 activation by MDM2 antagonist Nutlin3a were investigated. Simultaneous blockade of MEK and MDM2 signaling by AZD6244 and Nutlin3a triggered synergistic proapoptotic responses in AML cell lines (CI = 0.06 ± 0.03 and 0.43 ± 0.03 in OCI/AML3 and MOLM13 cells, respectively) and in primary AML cells (CI = 0.52 ± 0.01). Mechanistically, the combination upregulated levels of BH3-only proteins Puma and Bim, in part via transcriptional up-regulation of the FOXO3a transcription factor. Suppression of Puma and Bim by short interfering RNA rescued OCI/AML3 cells from AZD/Nutlin-induced apoptosis. These results strongly indicate therapeutic potential of combined MEK/MDM2 blockade in AML and implicate Puma and Bim as major regulators of AML cell survival.