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
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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
Jian-Qing Gao, email: [email protected]
Keywords: metformin; doxorubicin; drug resistance; mitochondrial toxicity; P-glycoprotein
Received: September 04, 2017 Accepted: November 16, 2017 Published: December 08, 2017
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.
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