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Int J Biol Sci 2017; 13(6):794-803. doi:10.7150/ijbs.18969 This issue Cite

Research Paper

Berberine Reverses Hypoxia-induced Chemoresistance in Breast Cancer through the Inhibition of AMPK- HIF-1α

Yue Pan¹, Dan Shao¹, Yawei Zhao¹, Fan Zhang¹, Xiao Zheng¹, Yongfei Tan¹, Kan He¹, Jing Li^1✉, Li Chen^{1, 2✉}

1. Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China;
2. School of Nursing, Jilin University, Changchun 130020, China.

✉ Corresponding authors: Dr. Li Chen, Department of Pharmacology, Basic College of Medicine, Jilin University, 126 Xinmin Street, Changchun 130021, People's Republic of China; E-mail: chenledu.cn Telephone/fax: +86 431 85619366. Dr. Jing Li, Department of Pharmacology, Basic College of Medicine, Jilin University, 126 Xinmin Street, Changchun 130021, People's Republic of China; E-mail: lijingedu.cn Telephone/fax: +86 431 85619799. More

Abstract

Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. Chemoresistance is common and inevitable after a variable period of time. Therefore, chemosensitization is a necessary strategy on drug-resistant breast cancer. In this study, MCF-7 breast cancer cell was cultured under hypoxia for a week to induce the resistance to doxorubincin (DOX). The effect of different doses of berberine, a traditional Chinese medicine, on DOX sensitivity to MFC-7/hypoxia cells was observed. We found that hypoxia increased DOX resistance on breast cancer cells with the AMPK activation. Low-dose berberine could resensitize DOX chemosensitivity in MCF-7/hypoxia cell, however, high-dose berberine directly induced apoptosis. The intriguing fact was that the protein expressions of AMPK and HIF-1α were down-regulated by berberine, either low dose or high dose. But the downstream of HIF-1α occurred the bifurcation dependent on the dosage of berberine: AMPK-HIF-1α-P-gp inactivation played a crucial role on the DOX chemosensitivity of low-dose berberine, while AMPK-HIF-1α downregulaton inducing p53 activation led to apoptosis in high-dose berberine. These results were consistent to the transplanted mice model bearing MCF-7 drug-resistance tumor treated by berberine combined with DOX or high-dose berberine alone. This work shed light on a potentially therapeutic attempt to overcome drug-resistant breast cancer.

Keywords: berberine, hypoxia, breast cancer resistance, AMPK, HIF-1α.

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