Authors: Alasdair C Cooper Ian N Fleming Su M Phyu Tim A D Smith
Publish Date: 2015/01/13
Volume: 141, Issue: 9, Pages: 1523-1532
Abstract
Metformin currently undergoing clinical trials as an adjuvant for the treatment of breast cancer modulates the activity of key intracellular signalling molecules which affect 218FFluoro2deoxydglucose 18FFDG incorporation Here we investigate the effect of drugs used in the treatment of breast cancer combined with metformin on 18FFDG incorporation in HER2 or HER1overexpressing breast cancer cells to determine whether or not metformin may obscure changes in 18FFDG incorporation induced by clinically utilised anticancer drugs in the treatment of breast cancerThree breast cancer cell lines expressing HER2 and one HER2 negative but HER1 positive were exposed to metformin doxorubicin and trastuzumab or cetuximab Cytotoxicity was measured by the MTT assay Expression of active phospho AMPK PKB Akt and ERK was determined by Western blotting 18FFDG incorporation by cells exposed to drug combinations with metformin was determined Glucose transport was assessed by measuring the initial rate of uptake of 3HOmethyldglucose 3HOMG Phosphorylation of 18FFDG was determined in intact cells after exposure to 18FFDGPhosphoAMPK was increased by metformin in all cell lines whilst phosphoAkt and phosphoERK expressions were decreased in two Metformin treatment increased 18FFDG incorporation in all cell lines and treatment with antiHER antibodies or doxorubicin only produced minor modulations in the increase induced by metformin alone Glucose transport was increased in BT474 cells and decreased in SKBr3 and MDAMB468 cells after treatment with metformin The fraction of phosphorylated 18FFDG was increased in metformintreated cells compared with controls suggesting that hexokinase efficiency was increased by metforminThis is the first study to show that increased 18FFDG incorporation by breast cancer cells induced by metformin overwhelms the effect of doxorubicin and antiHER treatments on 18FFDG incorporation Metformininduced increased 18FFDG incorporation was consistently associated with enhanced 18FFDG phosphorylation
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