Cooperative Modulation of the NF‐κB and p53 Pathways by Metronomic Cyclophosphamide and Metformin Inhibits Ehrlich Carcinoma Progression and Enhances Systemic Immunity

This study investigates the cooperative antitumor potential of combining metronomic cyclophosphamide (MTm-CTX) with the metabolic modifier metformin (MET) in a murine model of mammary carcinoma. While metronomic chemotherapy offers a reduced toxicity profile, its efficacy as a monotherapy is often limited by compensatory inflammatory signaling. We hypothesized that metabolic intervention with metformin could sensitize tumor cells to metronomic dosing by modulating key survival and immune pathways. Using mice bearing Ehrlich solid carcinoma (ESC), we evaluated the effects of MTm-CTX and MET, both individually and in combination, on tumor progression and the underlying molecular landscape. Our results demonstrate that the combination therapy significantly inhibits tumor growth, achieving a marked 65% reduction in tumor volume compared to the control group. Mechanistically, the combined regimen was associated with an apoptotic shift, characterized by the upregulation of p53 and the significant downregulation of survivin and Ki-67 expression. Furthermore, the treatment effectively modulated the tumor microenvironment by suppressing NF-κB, TNF-α, and IL-6 expression. Notably, this local tumor suppression is coupled with enhanced systemic cytotoxic immunity, marked by a significant upregulation of splenic Granzyme B alongside a numerical upward trend in interferon-gamma (IFN-γ) expression. Quantitative histopathological analysis confirmed substantial tumor regression and reduced viability in the combination group. These findings provide compelling evidence that the MTm-CTX and MET combination acts through a coordinated alternation of apoptotic and immune-inflammatory pathways. This study establishes a scientifically grounded framework for a potentially promising, cost-effective, and low-toxicity chemo-metabolic strategy worthy of further exploration in breast cancer management.