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

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 Li1✉, Li Chen1, 2✉

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


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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How to cite this article:
Pan Y, Shao D, Zhao Y, Zhang F, Zheng X, Tan Y, He K, Li J, Chen L. Berberine Reverses Hypoxia-induced Chemoresistance in Breast Cancer through the Inhibition of AMPK- HIF-1α. Int J Biol Sci 2017; 13(6):794-803. doi:10.7150/ijbs.18969. Available from