Promoted Efficacy for Breast Cancer Cell Line Killing via the Combination of Metformin and GM-CSF-Expressing...

Breast cancer, a world serious health issue of women and rarely men, is in demand of effective and breakthrough treatment approaches. Oncolytic virotherapy, especially herpes simplex virus type 1 (HSV-1) that expresses granulocyte-macrophage colony-stimulating factor (GM-CSF), has shown promise in cancer therapy. Metformin, an antidiabetic drug, has also reflected anticancer features. Hence, in this scientific project, we intended to evaluate the synergistic influences of combination of GM-CSF-expressing oncolytic HSV-1 (OHSV-GM-CSF) with metformin in cell lines related to breast cancer. To our knowledge, this is the first study to explore the potential therapeutic interplay between OHSV-GM-CSF and metformin, suggesting a unique approach to enhance oncolytic virotherapy in the treatment of this malignancy. For this purpose, recombinant HSV-1 viruses expressing GM-CSF were generated, and their effectiveness, both with and without metformin, was assessed on breast cancer cell lines, including MCF7 (hormone receptor-positive) and MDA-MB231 (triple-negative). Cytotoxicity, apoptosis, and immune activation were explored using MTT assays, flow cytometry, and ELISA. Also, peripheral blood mononuclear cells (PBMCs) were used to examine immune responses. Co-treatment with OHSV-GM-CSF and metformin significantly improved the cytotoxic impacts on breast cancer cells, elevated apoptosis, and potentiated immune activation compared to each treatment separately. GM-CSF expression was strong, and the production of interferon-γ (IFN-γ) in PBMCs was significantly higher in the combination group. Moreover, metformin further promoted the cytotoxic and immunostimulatory impacts of OHSV-GM-CSF. The combination of OHSV-GM-CSF and metformin reveals synergistic anticancer influences, promoting cytotoxicity, immune activation, and PBMC proliferation, suggestive of a promising approach for breast cancer therapy that necessitates further preclinical and clinical investigation. This strategy holds clear promise for future clinical application and warrants prioritization in translational cancer research.

Breast cancer cells (i.e., MCF7 and MDA-MB231) infected with a combination of recombinant HSV-1 viruses that express granulocyte-macrophage colony-stimulating factor (GM-CSF) and metformin exhibit a synergistic effect in promoting the expression of interferon-ϒ (IFN-ϒ) found within peripheral blood mononuclear cells (PBMCs) and exerting apoptotic and cytotoxic effects in the mentioned malignant cells.

The online version contains supplementary material available at 10.1007/s12088-025-01523-7.