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

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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.

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Acknowledgments

This work was supported by the funds raised through the Yayasan Sime Darby LPGA Tournament, donors of Cancer Research Initiatives Foundation and the Ministry of Higher Education Grant [UM.C/HIR/MOHE/06 and ERGS/1/2013/SKK01/IMU/02/1].

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    Authors and Affiliations

    1. Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia

      Jaslyn Sian-Siu Soo & Soo-Hwang Teo

    2. Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia

      Jaslyn Sian-Siu Soo, Char-Hong Ng, Yew-Ching Teh, Mee-Hoong See, Nur Aishah Mohd Taib, Cheng-Har Yip & Soo-Hwang Teo

    3. Breast Cancer Research Unit, Faculty of Medicine, University Malaya Medical Centre, University Malaya Cancer Research Institute, University of Malaya, 50603, Kuala Lumpur, Malaysia

      Jaslyn Sian-Siu Soo, Char-Hong Ng, Yew-Ching Teh, Mee-Hoong See, Nur Aishah Mohd Taib, Cheng-Har Yip & Soo-Hwang Teo

    4. Center for Cancer and Stem Cell Research, International Medical University, 126 Jalan 19/155B, 57000, Bukit Jalil, Kuala Lumpur, Malaysia

      Si Hoey Tan, Boon-Shing Tan, Felicia Fei-Lei Chung, Ling-Wei Hii & Chee-Onn Leong

    5. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

      Boon-Shing Tan

    6. Department of Clinical Oncology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia

      Rozita Abdul Malik & Gwo-Fuang Ho

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    Soo, J.SS., Ng, CH., Tan, S.H. et al. Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells. Apoptosis 20, 1373–1387 (2015). https://doi.org/10.1007/s10495-015-1158-5

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