Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells

Abstract

Metformin, an AMPK activator, has been reported to improve pathological response to chemotherapy in diabetic breast cancer patients. To date, its mechanism of action in cancer, especially in cancer stem cells (CSCs) have not been fully elucidated. In this study, we demonstrated that metformin, but not other AMPK activators (e.g. AICAR and A-769662), synergizes 5-fluouracil, epirubicin, and cyclophosphamide (FEC) combination chemotherapy in non-stem breast cancer cells and breast cancer stem cells. We show that this occurs through an AMPK-dependent mechanism in parental breast cancer cell lines. In contrast, the synergistic effects of metformin and FEC occurred in an AMPK-independent mechanism in breast CSCs. Further analyses revealed that metformin accelerated glucose consumption and lactate production more severely in the breast CSCs but the production of intracellular ATP was severely hampered, leading to a severe energy crisis and impairs the ability of CSCs to repair FEC-induced DNA damage. Indeed, addition of extracellular ATP completely abrogated the synergistic effects of metformin on FEC sensitivity in breast CSCs. In conclusion, our results suggest that metformin synergizes FEC sensitivity through distinct mechanism in parental breast cancer cell lines and CSCs, thus providing further evidence for the clinical relevance of metformin for the treatment of cancers.

Stemness in Cancer: Stem Cells, Cancer Stem Cells, and Their Microenvironment

“…New pharmacological combinations of compounds already available on the market to target diseases other than cancer could have a significant impact on hindering tumor progression. For instance, the use of metformin, commonly used to treat type II diabetes, in combination with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), greatly affects CSCs' ATP production, thereby impairing the cell repair mechanisms of DNA damage induced by FEC [190]. …”

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

“…Although AMPK-independent effects have been reported3132, Metformin acts through its effect on AMPK-dependent signaling have also been shown in several studies282930. Because of this, we next examined the relevant molecular mechanism by solamargine in the presence or absence of metformin.…”

“…Metformin, the most widely used drug in treatment of type 2 diabetes, has been shown to inhibit growth of different cancer types in several studies through AMPK-dependent and -independent signaling pathways2829303132. Herein, we also asked whether combination of known AMPK activator metformin and solamargine could have enhanced effect.…”

On metabolic reprogramming and tumor biology: A comprehensive survey of metabolism in breast cancer

“…However, since both drugs have been widely used in clinical diagnostic or therapeutic settings for decades, clinical application of the drug combination should be able to follow promptly. Metformin has further been shown to greatly improve the anti-cancer efficacy of chemotherapeutic drugs commonly used in breast cancer, often allowing reduced dosage regimens [164, 165]. Moreover, combinations with PI3K pathway inhibitors, e.g.…”