Oncotarget

Research Papers:

Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer

Bing Liu, XinPing Huang, YunLong Hu, TingTing Chen, BoYa Peng, NingNing Gao, ZhenChao Jin, TieLiu Jia, Na Zhang, ZhuLin Wang and GuangYi Jin _

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Oncotarget. 2016; 7:58038-58050. https://doi.org/10.18632/oncotarget.10846

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Abstract

Bing Liu1,2,3,*, XinPing Huang1,2,3,*, YunLong Hu1,2,3, TingTing Chen1,2,3, BoYa Peng1,2,3, NingNing Gao1,2,3, ZhenChao Jin1,2,3, TieLiu Jia1,2,3, Na Zhang4, ZhuLin Wang5, GuangYi Jin 1,2,3

1National-Regional Key Technology Engineering Laboratory for Synthetic Biology of Medicine, Cancer Research Center, Shenzhen University, Shenzhen, China

2Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen, China

3The Cancer Research Center, Shenzhen University, Shenzhen, China

4Department of Pathophysiology, Chongqing Medical University, Chongqing, China

5Shenzhen Conjugenix Pharma-Tech Co. Ltd, Guangdong, China

*These authors have contributed equally to this work

Correspondence to:

Guangyi Jin, email: [email protected]

Keywords: breast cancer, EGFR, tyrosine kinases, ethacrynic acid

Received: December 08, 2015     Accepted: June 29, 2016     Published: July 26, 2016

ABSTRACT

Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the α,β-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/β-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer.


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