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Exploration of Anticancer Mechanism of 2-Deoxyglucose in Cultured Bladder Cancer Cells Introduction and Objectives: More than 90% of bladder cancers in the United States are transitional cell carcinoma (TCC). Approximately 70% of TCC presents as superficial bladder tumor and are treated by transurethral resection. However, 50%-75% of those patients will recur within 5 years and approximately 10% will progress to muscle invasive disease. The primary goal in the treatment of superficial disease is therefore to prevent disease recurrence and progression. The glucose analog 2-deoxyglucose (2DG) has been studied as a potential anticancer agent that could target the metabolic pathway; however its anticancer mechanism has not yet been completely elucidated. Accordingly, we explored the anticancer effect and mechanism of 2DG in bladder cancer cells in vitro. Materials and Methods: Human bladder cancer 5637 cells were cultured with varying concentrations of 2DG (0-5 mM) and cell viability was assessed by MTT assay. To explore the anticancer mechanism of 2DG, several critical cellular events, such as glycolysis, specific signaling pathways, oxidative stress, and apoptosis, were further investigated. Results: 2DG treatment for 72-h resulted in a 57-83% reduction in cell viability in a dose-dependent manner. Activity of glyceraldehyde 3-phosphate dehydrogenase (G3PDH), one of the key glycolytic enzymes, declined to ~55% and the lactate level was also decreased to ~35% with 24-h 2DG (1 mM) treatment, indicating an inhibition of glycolysis. Concurrently, two signaling pathways, via AMP-activated protein kinase (AMPK) and protein kinase B (Akt), were modulated by 2DG, presumably accounting for the cell viability reduction. Malondialdehyde (MDA) assay showed that 2DG exposure elevated the cellular MDA levels to ~2.3-fold greater than that in controls, implying severe oxidative stress exerted on cells. Western blots further revealed that 2DG treatment led to activation of both caspase-3 and poly(ADP-ribose)-polymerase, indicating induction of apoptosis. Conclusions: This study demonstrates that 2DG has anticancer activity on bladder cancer 5637 cells and its anticancer mechanism involves diverse cellular effects, such as glycolysis inhibition, modulation of AMPK and Akt signaling pathways, exertion of oxidative stress, and induction of apoptosis. Therefore, 2DG appears to be an effective anticancer agent that may provide an alternative therapeutic modality for superficial bladder cancer.