Abstract
Targeting cancer cell metabolism is a new promising strategy to fight cancer. Metformin, a widely used antidiabetic agent, exerts antitumoral and antiproliferative action. In this study, the addition of metformin to 2-deoxyglucose (2DG) inhibited mitochondrial respiration and glycolysis in prostate cancer cells leading to a severe depletion in ATP. The combination of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone, leading to 96% inhibition of cell viability in LNCaP prostate cancer cells. In contrast, a moderate effect on cell viability was observed in normal prostate epithelial cells. At the cellular level, the combination of metformin and 2DG induced p53-dependent apoptosis via the energy sensor pathway AMP kinase, and the reexpression of a functional p53 in p53-deficient prostate cancer cells restored caspase-3 activity. In addition to apoptosis, the combination of metformin and 2DG arrested prostate cancer cells in G(2)-M. This G(2)-M arrest was independent of p53 and correlated with a stronger decrease in cell viability than obtained with either drug. Finally, metformin inhibited 2DG-induced autophagy, decreased beclin 1 expression, and triggered a switch from a survival process to cell death. Our study reinforces the growing interest of metabolic perturbators in cancer therapy and highlights the potential use of the combination of metformin and 2DG as an anticancerous treatment.
Highlights
Current treatments for advanced prostate cancer are limited, with drug resistance and toxicity requiring novel molecular therapeutics drugs directed against new cellular targets
Metformin accelerated glucose depletion from medium more severely in LNCaP than P69 cells (Fig. 1B) and lactate concentration augmented by 73% in the culture medium of LNCaP compared with 28% in P69 (Fig. 1C)
These results show that, as a consequence of complex 1 inhibition, metformin significantly increases glycolysis in prostate cancer cells and to a lesser extent in normal cells
Summary
Current treatments for advanced prostate cancer are limited, with drug resistance and toxicity requiring novel molecular therapeutics drugs directed against new cellular targets. Alterations in cancer cell metabolism are intricately linked to the principal hallmarks of cancer [1]. Most cancer cells use elevated amount of glucose for anabolic reactions and are more dependent on aerobic glycolytic. Metabolism to generate ATP than on mitochondrial metabolism. These biological alterations present a major challenge in cancer treatment, as exemplified by the resistance of cancer cells to chemotherapeutic agents and radiation therapy in hypoxic environment [1]. The increased dependency on glycolysis for energy generation provides a biochemical basis to preferentially kill the malignant cells by inhibition of glycolysis
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