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

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

Apoptosis : an international journal on programmed cell death (2015-08-16)
Jaslyn Sian-Siu Soo, Char-Hong Ng, Si Hoey Tan, Rozita Abdul Malik, Yew-Ching Teh, Boon-Shing Tan, Gwo-Fuang Ho, Mee-Hoong See, Nur Aishah Mohd Taib, Cheng-Har Yip, Felicia Fei-Lei Chung, Ling-Wei Hii, Soo-Hwang Teo, Chee-Onn Leong
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
AICAR, ≥98% (HPLC), powder
Sigma-Aldrich
Epirubicin hydrochloride, ≥90% (HPLC)
Sigma-Aldrich
Hydrocortisone, γ-irradiated, powder, BioXtra, suitable for cell culture
Sigma-Aldrich
Hydrocortisone, BioReagent, suitable for cell culture
Sigma-Aldrich
Hydrocortisone, ≥98% (HPLC)
Sigma-Aldrich
Fluorouracil, meets USP testing specifications
Sigma-Aldrich
1,1-Dimethylbiguanide hydrochloride, 97%
Sigma-Aldrich
5-Fluorouracil, ≥99% (HPLC), powder
Sigma-Aldrich
Hydrocortisone, meets USP testing specifications
Sigma-Aldrich
Cyclophosphamide monohydrate, bulk package
Sigma-Aldrich
Cyclophosphamide monohydrate, ISOPAC®