Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells.
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.
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia.
Jaslyn Sian-Siu
JS
Soo
Char-Hong
CH
Ng
Si Hoey
SH
Tan
Rozita Abdul
RA
Malik
Yew-Ching
YC
Teh
Boon-Shing
BS
Tan
Gwo-Fuang
GF
Ho
Mee-Hoong
MH
See
Nur Aishah Mohd
NA
Taib
Cheng-Har
CH
Yip
Felicia Fei-Lei
FF
Chung
Ling-Wei
LW
Hii
Soo-Hwang
SH
Teo
Chee-Onn
CO
Leong
D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D003520:Cyclophosphamide / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004338:Drug Combinations; D004357:Drug Synergism; D053595:Embryonic Stem Cells / Q000378:metabolism; D015251:Epirubicin / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism; D008168:Lung / Q000166:cytology; D008687:Metformin / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011753:Pyrones / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D011753:Pyrones; D012265:Ribonucleotides; D013876:Thiophenes; D019344:Lactic Acid; D000620:Aminoimidazole Carboxamide; D015251:Epirubicin; D000255:Adenosine Triphosphate; D003520:Cyclophosphamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005947:Glucose; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile; D005472:Fluorouracil