Is targeting glycolysis with 2-deoxyglucose a viable therapeutic approach to bladder cancer?

Purpose: Although several therapeutic options for bladder cancer are available, the poor efficacy and palpable side effects are a major concern. Establishing a more effective intervention is urgently demanded. Glycolysis is considered a strategic target and has been often investigated in various cancers. Particularly, 2-deoxyglucose (2DG), a glycolysis inhibitor, has been intensely studied and shown to be encouraging and promising. Accordingly, we investigated how targeting glycolysis with 2DG would be effective on bladder cancer cells. Methods: Bladder cancer 5637 cells were employed and cell viability was determined by MTT assay.  To explore the anticancer mechanism of 2DG linked to glycolysis, two glycolytic parameters of hexokinase (HK) activity and ATP synthesis, metabolic signaling pathways, and induction of apoptosis were examined. Whether 2DG may potentiate several chemotherapeutic drugs being clinically used was also assessed for its possible chemosensitizing effect. Results: A dose-dependent study of 2DG showed a 23-80% reduction in cell viability.  HK activity and cellular ATP level were decreased by ~46% and ~56% with 2DG, respectively, indicating the glycolysis inhibition.  AMP-activated protein kinase was activated while protein kinase B was inactivated and also mammalian target of rapamycin was inhibited with 2DG.  These modulations would lead to the growth cessation and the cell viability reduction. In fact, the down-regulation of anti-apoptotic bcl-2 and the up-regulation of pro-apoptotic Bax in 2DG-treated cells indicated induction of apoptosis. Moreover, chemotherapeutic drugs with poor cytotoxic activity were selectively sensitized with 2DG, resulting in a significantly improved cell viability reduction. Conclusion: 2DG has anticancer activity on bladder cancer cells and its anticancer mechanism involves the glycolysis inhibition, the modulations of certain signaling pathways, and induction of apoptosis. Additionally, 2DG has a chemosensitizing effect when combined with drugs. Thus, targeting glycolysis with 2DG appears to be an alternative, viable therapeutic approach to bladder cancer.