請用此 Handle URI 來引用此文件: http://hdl.handle.net/11455/40284
標題: Emodin enhances gefitinib-induced cytotoxicity via Rad51 downregulation and ERK1/2 inactivation
作者: Chen, R.S.
莊秀美
Jhan, J.Y.
Su, Y.J.
Lee, W.T.
Cheng, C.M.
Ciou, S.C.
Lin, S.T.
Chuang, S.M.
Ko, J.C.
Lin, Y.W.
關鍵字: Rad51
Emodin
Gefitinib
ERK1/2
Non-small cell lung cancer
cell lung-cancer
growth-factor receptor
tyrosine kinase inhibitors
homologous recombination
breast-cancer
dna-damage
in-vitro
induced
apoptosis
pathway
repair
期刊/報告no:: Experimental Cell Research, Volume 315, Issue 15, Page(s) 2658-2672.
摘要: 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.
URI: http://hdl.handle.net/11455/40284
ISSN: 0014-4827
文章連結: http://dx.doi.org/10.1016/j.yexcr.2009.06.002
顯示於類別:生物醫學研究所

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