Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on acute myeloid leukemia precursors
Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on acute myeloid leukemia precursors
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DOI：
10.1182/blood-2013-01-477216
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发表时间：
2013-05-02
期刊：
影响因子：
20.3
通讯作者：
Platanias, Leonidas C.
中科院分区：
文献类型：
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作者：
Altman, Jessica K.;Szilard, Amy;Platanias, Leonidas C.
Mnk激酶调节真核起始因子4 E（eIF 4 E）的磷酸化和活化，eIF 4 E是一种在信使RNA翻译起始中起关键作用的蛋白质，其活性对于各种细胞功能至关重要。eIF 4 E在急性髓性白血病（AML）中失调，其异常活性有助于白血病发生。我们确定了最近被证明是一种独特的Mnk抑制剂的抗真菌剂cercosporamide是否具有抗白血病特性。用尾孢酰胺处理AML细胞导致eIF 4 E磷酸化的剂量依赖性抑制。尾孢酰胺对Mnk激酶活性和eIF 4 E磷酸化的这种抑制导致对来自AML患者的原始白血病祖细胞（CFU-L）的剂量依赖性抑制作用，并增强阿糖胞苷（Ara-C）或雷帕霉素的哺乳动物靶（mTOR）复合物1抑制的抗白血病性质。类似地，尾孢酰胺与阿糖胞苷的组合在体内异种移植小鼠模型中导致增强的抗白血病应答。总之，这项工作表明，独特的Mnk抑制剂尾孢酰胺抑制eIF 4 E的磷酸化，并表现出抗白血病作用，支持未来的临床转化努力，涉及Mnk抑制剂与阿糖胞苷和/或mTOR抑制剂的组合用于治疗AML。
Mnk kinases regulate the phosphorylation and activation of the eukaryotic initiation factor 4E (eIF4E), a protein that plays key roles in the initiation of messenger RNA translation and whose activity is critical for various cellular functions. eIF4E is deregulated in acute myeloid leukemia (AML), and its aberrant activity contributes to leukemogenesis. We determined whether cercosporamide, an antifungal agent that was recently shown to act as a unique Mnk inhibitor, exhibits antileukemic properties. Treatment of AML cells with cercosporamide resulted in a dose-dependent suppression of eIF4E phosphorylation. Such suppression of Mnk kinase activity and eIF4E phosphorylation by cercosporamide resulted in dose-dependent suppressive effects on primitive leukemic progenitors (CFU-L) from AML patients and enhanced the antileukemic properties of cytarabine (Ara-C) or mammalian target of rapamycin (mTOR) complex 1 inhibition. Similarly, the combination of cercosporamide with cytarabine resulted in enhanced antileukemic responses in a xenograft mouse model in vivo. Altogether, this work demonstrates that the unique Mnk inhibitor cercosporamide suppresses phosphorylation of eIF4E and exhibits antileukemic effects, in support of future clinical-translational efforts involving combinations of Mnk inhibitors with cytarabine and/or mTOR inhibitors for the treatment of AML.