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The clinical use of doxorubicin (DOX) is limited due to its systemic side effects and drug resistance. Recent evidence suggests that metformin prevents and controls certain but not all types of cancer. The beneficial use of metformin in combination with some chemotherapeutic agents has been reported. The aim of this study is to investigate the influence of metformin on DOX-induced effects in human prostate DU145 cancer cells and clarify its molecular mechanisms. For this purpose, DU145 cells were treated with DOX or metformin, either alone or in combination with each other. The proliferation of DU145 cells was inhibited by DOX-alone and metformin-alone treatment in a time and dose-dependent manner. Metformin could enhance the cytotoxicity of DOX by increasing DOX cellular uptake and cell cycle arrest at G1/S checkpoint which is associated with the enhancement of p21 protein expression. Moreover, metformin could elevate DOX-induced apoptosis in DU145 cells in a concentration-dependent manner and DOX-induced caspase-3 activity. These findings suggest that the combined treatment of metformin with DOX potentiates the anticancer efficacy of DOX in DU145 cells via inhibiting ABCB1 function, cell cycle arrest at G1/S transition and apoptosis induction.Metformin increased the cytotoxicity and cellular uptake of DOX in DU145 cells.A combination of DOX and metformin induced an increase in the sub-G1 fraction.Metformin enhanced DOX-induced apoptosis via upregulation of caspase-3 and p21.