標題: Modulation of Rad51, ERCC1, and thymidine phosphorylase by emodin result in synergistic cytotoxic effect in combination with capecitabine
作者: Ko, Jen-Chung
Tsai, Min-Shao
Kuo, Ya-Hsun
Chiu, Yu-Fan
Weng, Shao-Hsing
Su, Ying-Chen
Lin, Yun-Wei
科技法律研究所
Institute of Technology Law
關鍵字: ERCC1;Rad51;Thymidine phosphorylase;Capecitabine;Emodin;ERK1/2;Cytotoxicity;Non-small cell lung cancer
公開日期: 1-Mar-2011
摘要: Thymidine phosphorylase (TP) is the rate-limiting enzyme for the activation of capecitabine (pro-drug of fluorouracil), and as a useful predictor of tumor response to capecitabine-based chemotherapy. Overexpression of Rad51 and ERCC1 induce resistance to chemotherapeutic agents. Emodin, one of the main bioactive anthraquinone derivatives in the roots and rhizomes of numerous plants, possesses potent antitumor effects. Accordingly, we aimed to explore the molecular mechanism of emodin enhances the capecitabine-induced cytotoxicity through controlling Rad51, ERCC1, and TP expression in human non-small cell lung cancer (NSCLC). The results show that capecitabine increases the phosphorylation of MKK1/2-ERK1/2 and protein levels of Rad51 and ERCC1 through enhancing the protein stability. Depletion of endogenous Rad51 or ERCC1 expression by specific small interfering RNA transfection significantly increases capecitabine-induced cell death and growth inhibition. Emodin enhances the capecitabine-induced cytotoxic effects through ERK1/2 inactivation and decreasing the Rad51 and ERCC1 protein levels induced by capecitabine. Enhancement of ERK1/2 signaling by constitutively active MKK1/2 (MKK1/2-CA) results in increasing Rad51 and ERCC1 protein levels and cell viability in NSCLC cell lines treated with emodin and capecitabine. Interestingly, emodin enhances TP mRNA and protein expression in capecitabine treated NSCLC cell lines, and depletion of the TP expression decreases the cytotoxic effects induced by capecitabine and emodin. We conclude that enhancing the cytotoxicity to capecitabine by emodin is mediated by down-regulation the expression of Rad51 and ERCC1 and up-regulation TP expression. (C) 2010 Elsevier Inc. All rights reserved.
URI: http://dx.doi.org/10.1016/j.bcp.2010.12.008
http://hdl.handle.net/11536/9265
ISSN: 0006-2952
DOI: 10.1016/j.bcp.2010.12.008
期刊: BIOCHEMICAL PHARMACOLOGY
Volume: 81
Issue: 5
起始頁: 680
結束頁: 690
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