Metformin in Caloric Restriction for cancer patients

Metformin demonstrates robust preclinical anti-cancer activity in ovarian cancer through multiple mechanisms that closely mimic caloric restriction effects.

A landmark 2015 study showed that metformin prevented aggressive ovarian cancer growth driven by high-energy diets by activating AMPK and SIRT1, followed by downstream inhibition of Akt-mTOR—the same pathways activated by caloric restriction.

Mechanisms of action include

- AMPK activation and mTOR pathway inhibition, disrupting cancer cell energy metabolism  

- Reduction in circulating insulin, IGF-1, and inflammatory cytokines (MCP-1, IL-6)  

- Epigenetic modifications, including reduction of H3K27 trimethylation  

- Enhanced chemotherapy sensitivity: metformin increased paclitaxel efficacy by 60% in mouse models 

- Metabolic reprogramming: inhibition of glycolysis, lipid synthesis, and mitochondrial complex I  

Metformin appears particularly effective in KRAS-mutant ovarian cancer (14% of cases), where it inhibits both glucose and glutamine metabolism.Combination with glutaminase inhibitors (CB-839) showed synergistic effects in KRAS-mutant models.  

Clinical evidence is encouraging. Epidemiological studies in diabetic women show associations between metformin use and reduced ovarian cancer risk and improved survival.

The critical question—application of metformin in non-diabetic patients—remains unanswered and requires prospective clinical trials.  

A 2026 review emphasizes metformin's promise as a repurposed drug for ovarian cancer, particularly given the disease's metabolic vulnerabilities, but notes that robust clinical trial data is lacking.