Metformin boosts doxorubicin efficacy and increases CD8 + T cell frequency in mouse breast cancer

Clin Transl Oncol. 2025 May;27(5):2060-2066. doi: 10.1007/s12094-024-03764-2. Epub 2024 Oct 29.

Abstract

Purpose: Breast cancer is a leading cause of cancer-related deaths among women worldwide. The presence and function of CD8 + T cells in the tumor microenvironment have been associated with better patient outcomes. Drug toxicity has posed a significant challenge to the clinical implementation of chemotherapy-based strategies in cancer treatment.

Methods: In this study, we employed flow cytometry to investigate the potential synergistic immunomodulatory effects on CD8 + T cells in a mouse model of breast cancer by combining metformin, an anti-diabetic medication, with doxorubicin.

Results: Through flow cytometry analysis, we observed that the combination of the two drugs led to an increased percentage of CD8 + T cells compared to either drug alone. The modulation of HIF-1α and STAT3 gene expression in the combination group further confirmed the efficacy of this approach.

Conclusions: Our findings suggest that combining metformin with doxorubicin can enhance the anticancer activity of doxorubicin and decrease its cytotoxicity in a 4T1 breast cancer mouse model.

Keywords: Breast cancer; CD8 + T cells; Combination therapy; Doxorubicin; Metformin.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic* / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols* / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / immunology
  • CD8-Positive T-Lymphocytes* / drug effects
  • CD8-Positive T-Lymphocytes* / immunology
  • Cell Line, Tumor
  • Doxorubicin* / administration & dosage
  • Doxorubicin* / pharmacology
  • Doxorubicin* / therapeutic use
  • Drug Synergism
  • Female
  • Flow Cytometry
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mammary Neoplasms, Experimental* / drug therapy
  • Mammary Neoplasms, Experimental* / immunology
  • Mammary Neoplasms, Experimental* / pathology
  • Metformin* / administration & dosage
  • Metformin* / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism

Substances

  • Metformin
  • Doxorubicin
  • Antibiotics, Antineoplastic
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • STAT3 Transcription Factor
  • Hif1a protein, mouse
  • Stat3 protein, mouse