Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death
Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death
复制标题
阻断细胞外信号调节激酶（ERK）通路可显著增强肿瘤细胞对组蛋白去乙酰化酶（HDAC）抑制剂诱导的细胞死亡的敏感性。
DOI：
10.1016/j.bbrc.2005.11.131
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发表时间：
2006-01-27
影响因子：
3.1
通讯作者：
Kohno, M
中科院分区：
文献类型：
--
作者：
Ozaki, K;Minoda, A;Kohno, M
细胞外信号调节激酶（ERK）通路的组成性激活与大量人类肿瘤细胞的肿瘤表型相关。尽管通过用有效的丝裂原激活蛋白激酶/ERK激酶（MEK）抑制剂处理此类肿瘤细胞来特异性阻断ERK通路可完全抑制其增殖，但其本身对诱导凋亡细胞死亡仅显示出适度的作用。然而，这些 MEK 抑制剂显着增强组蛋白脱乙酰酶 (HDAC) 抑制剂诱导细胞凋亡的功效：这种增强的细胞死亡仅在 ERK 途径被组成型激活的肿瘤细胞中观察到。 MEK 抑制剂的共同给药显着使肿瘤细胞对 HDAC 抑制剂诱导的活性氧产生敏感，这似乎介导了这些药物组合诱导的细胞死亡增强。这些结果表明MEK抑制剂和HDAC抑制剂的组合为治疗ERK途径被组成型激活的肿瘤细胞提供了有效的化疗策略。 (c) 2005 Elsevier Inc. 保留所有权利。
Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway is associated with the neoplastic phenotype of a large number of human tumor cells. Although specific blockade of the ERK pathway by treating such tumor cells with potent mitogen-activated protein kinase/ERK kinase (MEK) inhibitors completely suppresses their proliferation, it by itself shows only a modest effect on the induction of apoptotic cell death. However, these MEK inhibitors markedly enhance the efficacy of histone deacetylase (HDAC) inhibitors to induce apoptotic cell death: such an enhanced cell death is observed only in tumor cells in which the ERK pathway is constitutively activated. Co-administration of MEK inhibitor markedly sensitizes tumor cells to HDAC inhibitor-induced generation of reactive oxygen species, which appears to mediate the enhanced cell death induced by the combination of these agents. These results suggest that the combination of MEK inhibitors and HDAC inhibitors provides an efficient chemotherapeutic strategy for the treatment of tumor cells in which the ERK pathway is constitutively activated. (c) 2005 Elsevier Inc. All rights reserved.