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The tolerance to adriamycin of cancer as a common and stubborn obstacle occurred during curing breast cancer patients needs to be overcome. In the present study, we explored whether inhibiting the glucose transporter 1 (GLUT1) could restore the activity of adriamycin in breast cancer cell line MCF-7 resistant to adriamycin and the possible underlying mechanisms. Adriamycin-resistant cell line MCF-7/ADR was selected stepwise from the parental MCF-7 cells and the level of GLUT1 was measured. Then, the MCF-7/ADR cells were incubated with adriamycin, WZB117 (a specific GLUT1 inhibitor), or both. The viability, proliferation and apoptosis of cells and the level of glucose and lactate were measured, respectively. Finally, the cytosolic and mitochondrial proteins were isolated and the activity of the adenosine monophosphate-activated protein kinase (AMPK)/phosphorylated AMPK, mammalian target of rapamycin (mTOR)/phosphorylated mTOR, and apoptotic-related protein BCL-2-associated X protein (BAX), Bcl-2 was assayed by western blot. We found that WZB117 resensitized MCF-7/ADR to adriamycin and increased BAX translocated to mitochondria, which through activation of AMPK and inhibition of mTOR in a high probability. Inhibition of the GLUT1 could partially restore the antineoplastic effects of adriamycin in the adriamycin-resistant MCF-7 cell line possibly through activating the AMPK, downregulating the mTOR pathway, and increasing the BAX translocation to mitochondria.