The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma
The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma
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DOI：
10.1182/blood-2011-03-340109
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发表时间：
2011-07-28
期刊：
影响因子：
20.3
通讯作者：
Gartenhaus, Ronald B.
中科院分区：
文献类型：
--
作者：
Bhalla, Savita;Evens, Andrew M.;Gartenhaus, Ronald B.
RAS/RAF/MEK/ERK信号通路作为淋巴瘤的潜在治疗靶点在很大程度上尚未被探索。新型第二代抗MEK小分子AZD 6244下调了其直接下游靶点，即生发中心和非生发中心弥漫性大B细胞淋巴瘤（DLBCL）细胞系和原代细胞中的磷酸化ERK（pERK）。尽管存在MEK的组成性激活（CA），但仍观察到类似的pERK水平降低。因此，AZD 6244下调了几种淋巴瘤相关ERK底物，包括MCT-1、c-Myc、Bcl-2、Mcl-1和CDK1/2。AZD 6244在所有DLBCL细胞系和新鲜/原代细胞中诱导时间和剂量依赖性的抗增殖和凋亡（IC（50）100 nM-300 nM）。此外，在体内DLBCL SCID异种移植模型中，与对照相比，AZD 6244导致显著更少的肿瘤。细胞死亡与裂解的PARP、半胱天冬酶-8、半胱天冬酶-9和半胱天冬酶-3相关，细胞凋亡是半胱天冬酶依赖性的。此外，FoxO3a的稳定，BIM和BIA的激活以及c-Myc转录物的显著减少。此外，BIM的siRNA敲低废除了AZD6244相关的凋亡，而ERK的shRNA敲低最低限度地致敏细胞。最后，用CA-AKT转染OCI-LY3细胞或通过化学抑制（LY294002）操作AKT对AZD 6244诱导的细胞死亡的影响极小。总之，这些发现表明，新型抗MEK药物AZD 6244可诱导DLBCL细胞凋亡，且细胞死亡具有BIM依赖性。（血。2011; 118（4）：1052 - 1061）
The RAS/RAF/MEK/ERK signaling pathway has been largely unexplored as a potential therapeutic target in lymphoma. The novel 2nd generation anti-MEK small molecule, AZD6244, down-regulated its direct downstream target, phospho-ERK (pERK) in germinal center and nongerminal center diffuse large B-cell lymphoma (DLBCL) cell lines and primary cells. Similar decreased pERK levels were noted despite constitutive activation (CA) of MEK. Consequently, several lymphoma-related ERK substrates were down-regulated by AZD6244 including MCT-1, c-Myc, Bcl-2, Mcl-1, and CDK1/2. AZD6244 induced time-and dose-dependent antiproliferation and apoptosis in all DLBCL cell lines and fresh/primary cells (IC(50) 100nM-300nM). Furthermore, AZD6244 resulted in significantly less tumor compared with control in an in vivo DLBCL SCID xenograft model. Cell death was associated with cleaved PARP, caspases-8, -9, and -3, and apoptosis was caspase-dependent. In addition, there was stabilization of FoxO3a, activation of BIM and PUMA, and a significant decrease in c-Myc transcripts. Moreover, siRNA knockdown of BIM abrogated AZD6244-related apoptosis, while shRNA knockdown of ERK minimally sensitized cells. Finally, manipulation of AKT with transfection of OCI-LY3 cells with CA-AKT or through chemical inhibition (LY294002) had minimal effect on AZD6244-induced cell death. Altogether, these findings show that the novel anti-MEK agent, AZD6244, induced apoptosis in DLBCL and that cell death was BIM-dependent. (Blood. 2011; 118(4):1052-1061)