Oncotarget

Research Papers:

Metformin synergistically suppress tumor growth with doxorubicin and reverse drug resistance by inhibiting the expression and function of P-glycoprotein in MCF7/ADR cells and xenograft models

Ying Li, Meng Wang, Pei Zhi, Jian You and Jianqing Gao _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:2158-2174. https://doi.org/10.18632/oncotarget.23187

Metrics: PDF 679 views  |   HTML 1773 views  |   ?  


Abstract

Ying Li1,2, Meng Wang1,2, Pei Zhi1,2, Jian You1 and Jian-Qing Gao1,2

1Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China

2Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China

Correspondence to:

Jian-Qing Gao, email: gaojianqing@zju.edu.cn

Keywords: metformin; doxorubicin; drug resistance; mitochondrial toxicity; P-glycoprotein

Received: September 04, 2017     Accepted: November 16, 2017     Published: December 08, 2017

ABSTRACT

Acquired resistance to chemo-drugs remains a major obstacle to successful cancer therapy. Metformin, a well-documented drug for treating type II diabetes, was recently proposed as a novel agent for tumor treatment. In this study, we found that metformin suppressed MCF7/ADR, a doxorubicin-resistant breast cancer cell line, and acted synergistically with doxorubicin by reversing drug-resistant phenotypes both in vitro and in vivo. Metformin alone dose-dependently inhibited tumor growth, especially the stressful tumor microenvironment of glucose deficiency, and the cytotoxicity of metformin was markedly enhanced by increasing ROS production and ATP depletion. In addition, we found that metformin showed synergistic activity with doxorubicin against MCF7/ADR. Metformin increased nuclear doxorubicin accumulation and overcame drug resistance by down-regulating drug-resistant genes such as P-glycoprotein (Pgp). Metformin alone markedly inhibited MCF7/ADR tumor xenografts and demonstrated synergistic activity with doxorubicin in vivo by eliminating Ki67-positive cancer cells. In addition, metformin suppressed Pgp expression in vivo. In conclusion, our results suggested that metformin could potentially be used in the treatment of chemo-resistant tumors and could restore doxorubicin sensitivity.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 23187