Metabolic Blockade in Prostate Cancer: Repurposing SGLT2 Inhibitors as Dual Antitumor and Cardio-Protective Therapy

SGLT2 inhibitors, familiar as diabetes medications like dapagliflozin and canagliflozin, show promise against prostate cancer (and other solid tumors) through targeted metabolic disruption that exploits cancer cells’ addiction to glucose. Prostate tumors frequently overexpress SGLT2 transporters, enabling excessive glucose uptake that fuels the Warburg effect, where cancer cells convert glucose to lactate even in oxygen-rich environments to support rapid proliferation. By blocking these transporters, SGLT2 inhibitors starve prostate cancer cells of their primary energy source, reducing intracellular ATP levels by 40-50% and forcing reliance on inefficient oxidative phosphorylation pathways that trigger cell death.

In prostate cancer models like PC3 cells, dapagliflozin specifically inhibits Complex I of the mitochondrial electron transport chain, disrupting respiration and destabilizing mitochondrial membranes while activating AMPK—a master energy sensor that halts cell cycle progression in G1/S phase and promotes apoptosis. Mendelian randomization studies provide genetic evidence that SGLT2 inhibition lowers overall prostate cancer risk with an odds ratio of 0.56 (95% CI 0.38-0.82), extending protection against both advanced disease and early-onset cases, independent of diabetes status. This suggests inherent antitumor activity beyond glycemic control, as SGLT2 expression correlates with aggressive tumor behavior and poorer survival.

A pivotal pilot clinical trial at Washington University School of Medicine tests neoadjuvant dapagliflozin in 24 men with high-risk localized prostate cancer, administering 5 mg daily for six weeks before radical prostatectomy. Primary endpoints focus on tolerability and safety per CTCAE v5.0 criteria, with secondary measures including MRI-assessed tumor shrinkage, necrosis rates, and metabolic biomarkers like glucose, C-peptide, HbA1c, and glucagon—directly probing the drug’s impact on tumor metabolism.

Preclinical synergy amplifies this potential: combining SGLT2 inhibitors with chemotherapy or immunotherapy addresses prostate cancer’s metabolic resilience and immunosuppressive microenvironment. AMPK activation from SGLT2 blockade suppresses mTOR/PI3K/AKT signaling (pathways hyperactive in castration-resistant prostate cancer) while reducing hypoxia-driven T-cell exhaustion that hampers checkpoint inhibitors. In broader cancer cohorts with diabetes, SGLT2 use during immunotherapy slashed all-cause mortality from 59% to 21% (p=0.002), with zero cases of cardiotoxicity like myocarditis, a common prostate cancer therapy complication.

Safety remains favorable for prostate cancer patients, who often face cardiovascular risks from androgen deprivation or chemotherapy. Large meta-analyses confirm SGLT2 inhibitors reduce overall cancer incidence (RR 0.35, 95% CI 0.33-0.37) without elevating prostate-specific risks, while cutting heart failure hospitalizations.

Clinical trial.