Emodin enhances gefitinib-induced cytotoxicity via Rad51 downregulation and ERK1/2 inactivation
Emodin enhances gefitinib-induced cytotoxicity via Rad51 downregulation and ERK1/2 inactivation
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DOI：
10.1016/j.yexcr.2009.06.002
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发表时间：
2009-09-10
影响因子：
3.7
通讯作者：
Lin, Yun-Wei
中科院分区：
文献类型：
--
作者：
Chen, Ruey-Shyang;Jhan, Jhih-Yuan;Lin, Yun-Wei
大黄素是一种酪氨酸激酶抑制剂，是一种天然的蒽醌衍生物，存在于许多植物的根和根茎中。据报道，它对肺癌有抗癌作用。吉非替尼（易瑞沙）是一种用于人类非小细胞肺癌（NSCLC）的选择性表皮生长因子受体（EGFR）酪氨酸激酶抑制剂。然而，大黄素联合吉非替尼降低NSCLC细胞活力的分子机制尚不清楚。重组酶蛋白Rad51对同源重组修复至关重要，Rad51过表达对DNA双链断裂诱导的癌症治疗具有抗性。在本研究中，我们发现大黄素增强了吉非替尼对两种NSCLC细胞株A549和H1650的细胞毒性。低剂量2-10 μ M的大黄素不影响ERK1/2激活、mRNA和Rad51蛋白水平；然而，它通过增强Rad51蛋白的不稳定性，增强了吉非替尼诱导的磷酸化- erk1 /2和Rad51蛋白水平的降低。在吉非替尼和大黄素共处理下，组成活性MKK1/2载体（MKK1/2- ca）的表达显著挽救了磷酸化- erk1 /2和Rad51蛋白水平的降低以及细胞活力。在大黄素处理的H1650和A549细胞中，U0126（一种MKK1/2抑制剂）阻断ERK1/2激活可降低Rad51蛋白水平和细胞活力。通过转染si-Rad51 RNA降低Rad51的表达可增强大黄素的细胞毒性。相反，Rad51过表达可以保护细胞免受大黄素和吉非替尼诱导的细胞毒性作用。因此，大黄素-吉非替尼联合治疗可以作为治疗晚期肺癌的一种新的、更好的治疗方式的基础。(C) 2009爱思唯尔公司版权所有。
Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. It reportedly exhibits an anticancer effect on lung cancer. Gefitinib (Iressa) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for human non-small cell lung cancer (NSCLC). However, the molecular mechanism of how emodin combined with gefitinib decreases NSCLC cell viability is unclear. The recombinase protein Rad51 is essential for homologous recombination repair, and Rad51 overexpression is resistant to DNA double-strand break-inducing cancer therapies. In this study, we found that emodin enhanced the cytotoxicity induced by gefitinib in two NSCLC cells lines, A549 and H1650. Emodin at low doses of 2-10 mu M did not affect ERK1/2 activation, mRNA, and Rad51 protein levels; however, it enhanced a gefitinib-induced decrease in phospho-ERK1/2 and Rad51 protein levels by enhancing Rad51 protein instability. Expression of constitutively active MKK1/2 vectors (MKK1/2-CA) significantly rescued the reduced phospho-ERK1/2 and Rad51 protein levels as well as cell viability on gefitinib and emodin cotreatment. Blocking of ERK1/2 activation by U0126 (an MKK1/2 inhibitor) lowered Rad51 protein levels and cell viability in emodin-treated H1650 and A549 cells. Knockdown of Rad51 expression by transfection with si-Rad51 RNA enhanced emodin cytotoxicity. In contrast, Rad51 overexpression protected the cells from the cytotoxic effects induced by emodin and gefitinib. Consequently, emodin-gefitinib cotreatment may serve as the basis for a novel and better therapeutic modality in the management of advanced lung cancer. (C) 2009 Elsevier Inc. All rights reserved.