Targeting Glucose Metabolism in Bladder Cancer: Therapeutic Implications of 2-Deoxy-d-glucose

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Abstract
Bladder cancer is characterized by metabolic reprogramming, and enhanced glycolysis contributes to tumor progression and therapeutic resistance. Because the anticancer activity of 2-Deoxy-d-glucose (2-DG) has been reported in several malignancies, this study evaluated the antiproliferative and metabolism-modulating effects of 2-DG and their association with oxidative stress-related signaling in bladder cancer models. Human bladder cancer cell lines were examined using MTT assays, hexokinase (HK) activity assays, ATP measurements, DCF-DA-based reactive oxygen species (ROS) analysis, and Western blotting. RT112 and 253J cells were selected for mechanistic analyses, and the antitumor efficacy of 2-DG was further evaluated in xenograft models. Treatment with 2-DG reduced the metabolic activity of all five bladder cancer cell lines in a concentration-dependent manner and was associated with decreased HK activity and intracellular ATP levels. Increased ROS-sensitive fluorescence was accompanied by upregulation of TXNIP and BAX and downregulation of AKT and BCL-2, indicating a shift toward a pro-apoptotic pattern of apoptosis-related protein expression. In vivo, systemic administration of 2-DG significantly suppressed xenograft tumor growth without apparent body weight loss or histological abnormalities in the liver or kidneys. These findings suggest that 2-DG suppresses bladder cancer growth in association with metabolic disruption, increased ROS-sensitive fluorescence, TXNIP/AKT-related changes, and modulation of BAX/BCL-2 expression. However, additional studies are required to clarify the underlying mechanisms and further evaluate its safety profile.

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