Inhibition of glycolysis in cancer cells: A novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia

Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Research (Impact Factor: 9.33). 02/2005; 65(2):613-21.
Source: PubMed


Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect) due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Here, we report that inhibition of glycolysis severely depletes ATP in cancer cells, especially in clones of cancer cells with mitochondrial respiration defects, and leads to rapid dephosphorylation of the glycolysis-apoptosis integrating molecule BAD at Ser(112), relocalization of BAX to mitochondria, and massive cell death. Importantly, inhibition of glycolysis effectively kills colon cancer cells and lymphoma cells in a hypoxic environment in which the cancer cells exhibit high glycolytic activity and decreased sensitivity to common anticancer agents. Depletion of ATP by glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells, suggesting that deprivation of cellular energy supply may be an effective way to overcome multidrug resistance. Our study shows a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance. Because the Warburg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications.

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    • "However, the diminished MMP induced by XN is not accompanied by the decreased cellular ATP level (Fig. 3A); this might be due to the increased glycolysis levels in XN-treated cells (Fig. 3B and 3C). When the ability of cells to generate ATP through mitochondrial OXPHOS is compromised, cells increase their glycolytic activity to maintain their energy supply [34]. Here, we confirmed the compensatory effect of glycolysis on cell bioenergetics. "
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    • "Our recent studies in ovarian cancer found that ascorbate-induced oxidative stress damaged DNA and depleted ATP in ovarian cancer cells but not in ovarian epithelial cells (Ma et al. 2014). Owing to mitochondrial dysfunction, hypoxia in the tumor microenvironment, and oncogenic signals, cancer cells rely primarily on glycolysis for ATP production, so their ATP synthesis is not efficient compared with normal cells that primarily use oxidative phosphorylation (Warburg et al. 1927; Hyslop et al. 1988; Comelli et al. 2003; Ahmad et al. 2005; Xu et al. 2005; Pelicano et al. 2006). Therefore, these cancer cells are more susceptible to ascorbate-induced oxidative stress than normal cells. "
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    • "The system was referred to in the previous paper (Xu et al. 2005; Welser et al. 2010; Zhou et al. 2014). Briefly, BV2 microglia were seeded in 6-well plates at the density of 2 9 10 5 cells/well. "
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