標題: Tamoxifen enhances erlotinib-induced cytotoxicity through down-regulating AKT-mediated thymidine phosphorylase expression in human non-small-cell lung cancer cells
作者: Ko, Jen-Chung
Chiu, Hsien-Chun
Syu, Jhan-Jhang
Jian, Yi-Jun
Chen, Chien-Yu
Jian, Yun-Ting
Huang, Yi-Jhen
Wo, Ting-Yu
Lin, Yun-Wei
科技法律研究所
Institute of Technology Law
關鍵字: Thymidine phosphorylase;AKT;ERK1/2;Tamoxifen;Erlotinib;Non-small-cell lung cancer
公開日期: 1-Mar-2014
摘要: Tamoxifen is a triphenylethylene nonsteroidal estrogen receptor (ER) antagonist used worldwide as an adjuvant hormone therapeutic agent in the treatment of breast cancer. However, the molecular mechanism of tamoxifen-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. Thymidine phosphorylase (TP) is an enzyme of the pyrimidine salvage pathway which is upregulated in cancers. In this study, tamoxifen treatment inhibited cell survival in two NSCLC cells, H520 and H1975. Treatment with tamoxifen decreased TP mRNA and protein levels through AKT inactivation. Furthermore, expression of constitutively active AKT (AKT-CA) vectors significantly rescued the decreased TP protein and mRNA levels in tamoxifen-treated NSCLC cells. In contrast, combination treatment with PI3K inhibitors (LY294002 or wortmannin) and tamoxifen further decreased the TP expression and cell viability of NSCLC cells. Knocking down TP expression by transfection with small interfering RNA of TP enhanced the cytotoxicity and cell growth inhibition of tamoxifen. Erlotinib (Tarceva, OSI-774), an orally available small molecular inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is approved for clinical treatment of NSCLC. Compared to a single agent alone, tamoxifen combined with erlotinib resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells, accompanied with reduced activation of phospho-AKT and phospho-ERK1/2, and reduced TP protein levels. These findings may have implications for the rational design of future drug regimens incorporating tamoxifen and erlotinib for the treatment of NSCLC. (C) 2014 Elsevier Inc. All rights reserved.
URI: http://dx.doi.org/10.1016/j.bcp.2014.01.010
http://hdl.handle.net/11536/24015
ISSN: 0006-2952
DOI: 10.1016/j.bcp.2014.01.010
期刊: BIOCHEMICAL PHARMACOLOGY
Volume: 88
Issue: 1
起始頁: 119
結束頁: 127
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