Combination of metformin and parthenolide inhibits breast cancer in mice by apoptosis induction and angiogenesis inhibition.

BACKGROUND

Metformin (MET), a widely used antidiabetic agent, and parthenolide (PAR), a natural compound recognized for its anti-inflammatory properties, have both been extensively explored for their anticancer potential. The present study aimed to investigate the anticancer activity of their combination against breast cancer in vitro and in vivo.

METHODS

The antiproliferative effects of MET, PAR, and their combination were evaluated against a panel of breast cancer cell lines (EMT6/P, MDA-MB-231, and T47D) using the MTT assay. Synergistic interactions were assessed using the isobolographic method to calculate the combination index (CI). Apoptosis and angiogenesis were further investigated in T47D cells through caspase-3 activity assays and measurement of vascular endothelial growth factor (VEGF) levels, respectively. For in vivo assessment, EMT6/P cells were inoculated in BALB/c mice, and the antitumor effects of MET, PAR, and their combination were evaluated by monitoring tumor size. Treatment-related toxicity was assessed by measuring serum levels of aspartate transaminase (AST), alanine transaminase (ALT), and creatinine.

RESULTS

MET and PAR exhibited a clear synergistic antiproliferative interaction against all tested breast cancer cell lines, with varying degrees of synergism observed. In vivo, combination therapy produced a significant reduction in tumor size, with a cure rate of 50% and zero treatment-related mortality. The combination significantly induced caspase-3-dependent apoptosis and reduced VEGF expression compared to either agent alone. Serum AST, ALT, and creatinine levels in combination-treated tumor-bearing mice remained within normal ranges, supporting the safety of this regimen.

CONCLUSION

The combination of MET and PAR demonstrates synergistic anticancer activity against breast cancer both in vitro and in vivo, acting through apoptosis induction and angiogenesis inhibition. Given these promising findings, further studies are warranted to provide more comprehensive molecular and mechanistic characterization of this combination and to support its future clinical evaluation.