MEK1/2 Inhibition Suppresses Tamoxifen Toxicity on CNS Glial Progenitor Cells
MEK1/2 Inhibition Suppresses Tamoxifen Toxicity on CNS Glial Progenitor Cells
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DOI：
10.1523/jneurosci.2729-13.2013
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发表时间：
2013-09-18
影响因子：
5.3
通讯作者：
Noble, Mark
中科院分区：
文献类型：
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作者：
Chen, Hsing-Yu;Yang, Yin Miranda;Noble, Mark
越来越明显的是，多种抗癌药物的治疗常常与不良的神经系统后果相关。临床研究表明，即使接触他莫昔芬（TMX）（一种广泛用于乳腺癌治疗的公认的良性抗激素药物）也会导致认知功能障碍以及中枢神经系统代谢、海马体积和大脑结构的变化。我们发现TMX在体外对多种中枢神经系统细胞群具有毒性，并且还会增加胼胝体的细胞死亡，并减少小鼠脑室下区、海马齿状回和胼胝体的细胞分裂。我们进一步发现，MEK1/2 抑制在体外选择性地拯救原代胶质祖细胞免受 TMX 毒性，同时增强 TMX 对 MCF7 管腔人乳腺癌细胞的作用。在体内，MEK1/2 抑制可防止 TMX 诱导的全身治疗小鼠细胞死亡。我们的结果证明了这种被认为是良性的抗激素药物具有意想不到的细胞毒性，并为拯救 CNS 细胞免受 TMX 的不利影响提供了潜在的策略。
It is increasingly apparent that treatment with a variety of anticancer agents often is associated with adverse neurological consequences. Clinical studies indicate that exposure even to tamoxifen (TMX), a putatively benign antihormonal agent widely used in breast cancer treatment, causes cognitive dysfunction and changes in CNS metabolism, hippocampal volume, and brain structure. We found that TMX is toxic for a variety of CNS cell populations in vitro and also increased cell death in the corpus callosum and reduced cell division in the mouse subventricular zone, the hippocampal dentate gyrus, and the corpus callosum. We further discovered that MEK1/2 inhibition selectively rescued primary glial progenitors from TMX toxicity in vitro while enhancing TMX effects on MCF7 luminal human breast cancer cells. In vivo, MEK1/2 inhibition prevented TMX-induced cell death in systemically treated mice. Our results demonstrate unexpected cytotoxicity of this putatively benign antihormonal agent and offer a potential strategy for rescuing CNS cells from adverse effects of TMX.