Inhibition of bioenergetic metabolism by the combination of metformin and 2-deoxyglucose highly decreases viability of feline mammary carcinoma cells

Abstract

Feline mammary carcinoma (FMC) is a highly aggressive pathology that has been proposed as an interesting model of breast cancer disease, especially for the hormone refractory subgroup. Recently, cancer cell metabolism has been described as a hallmark of cancer cells. Here, we investigate the effects and mechanism of metabolic modulation by metformin (MET, anti-diabetic drug), 2-deoxyglucose (2DG, hexokinase inhibitor) or a combination of both drugs, MET/2DG on two established FMC cells lines: AlRB (HER2 (3 +) and Ki67 < 5%) and AlRATN (HER2 (−) and Ki67 > 15%). We found that treatments significantly decreased both FMC cells viability by up to 80%. AlRB resulted more sensitive to 2DG than AlRATN (IC50: 3.15 vs 6.32 mM, respectively). The combination of MET/2DG potentiated the effects of the individually added drugs on FMC cells. In addition, MET/2DG caused an increased in intracellular oxidants, autophagic vesicles and completely inhibited colony formation.Conversely, only MET significantly altered plasma membrane integrity, presented late apoptotic/necrotic cells and increased both glucose consumption and lactate concentration. Our results support further studies to investigate the potential use of this metabolic modulation approach in a clinical veterinary setting.