Exploiting Metabolic Vulnerabilities in Cancer with a Dual-Transporter-Targeted 2-Deoxyglucose Analogue for Low-Dose,...

Area of Science:

• Biochemistry
• Oncology
• Drug Development

Background:

• 2-deoxyglucose (2DG) shows promise as a cancer therapeutic but requires high doses, leading to toxicity.
• This limits its clinical translation due to the need to outcompete circulating glucose.

Purpose of the Study:

• To develop a novel 2DG conjugate to overcome dose-limiting toxicities.
• To enhance 2DG's anticancer efficacy by targeting multiple nutrient pathways simultaneously.

Main Methods:

• Covalently linked 2DG to 1,18-octadecanedioic acid (ODDA) to create 2DG-ODDA.
• Investigated dual-transporter uptake in 4T1 triple-negative breast cancer (TNBC) cells.
• Assessed in vitro cytotoxicity, apoptosis induction, and metabolic flux (ATP production).
• Evaluated in vivo tumor suppression in a preclinical model.

Main Results:

• 2DG-ODDA demonstrated significantly higher potency (16-fold lower IC50) than 2DG in vitro.
• The conjugate induced apoptosis and inhibited both glycolytic and mitochondrial ATP production.
• Low-dose subcutaneous 2DG-ODDA significantly suppressed tumor growth in vivo, while 2DG was inactive.

Conclusions:

• Dual nutrient-pathway targeting is a viable strategy to enhance glycolytic inhibitors' anticancer activity.
• 2DG-ODDA effectively exploits cancer's metabolic vulnerabilities, offering a potential therapeutic advantage.
• This approach overcomes the limitations of high-dose 2DG therapy by improving efficacy and reducing toxicity.