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.
Highlights
Cancer recurrence after conventional chemotherapy remains a major challenge in clinical therapy of breast cancer due to increased multidrug resistance
The results showed that metformin cytotoxicity in MCF7/ADR was significantly enhanced by glucose starvation but not hypoxia (Figure 3A), whereas doxorubicin cytotoxicity was not affected (Figure 3B)
The AMPK/mammalian target of rapamycin (mTOR) pathway is one of the most recognized anti-tumor mechanisms of metformin, so we investigated whether AMPK/mTOR activation is involved in overcoming drug resistance
Summary
Cancer recurrence after conventional chemotherapy remains a major challenge in clinical therapy of breast cancer due to increased multidrug resistance. It effectively inhibits tumor growth, it otherwise enhances tumor malignancy, leading to cancer recurrence and poor responses to many conventional chemo-drugs. Epidemiological studies have shown that metformin use is associated with a lower incidence and mortality of numerous cancers, in patients with type 2 diabetes [1, 2]. Accumulating pre-clinical evidence has shown the anti-tumor activity of metformin on different cancer cell lines, and registered clinical trials using metformin for cancer prevention or treatment have been approved [3, 4]. Metformin sensitizes tumor cells to traditional chemo-drugs as well as irradiation therapy [6,7,8]
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