Diosmetin Modulates EMT-Associated Plasticity and Fibroblast-Activation Markers in Parallel Breast Cancer In Vitro...

Metastasis remains the leading cause of mortality in breast cancer and is closely linked to epithelial-mesenchymal transition (EMT) and tumor microenvironment (TME)-associated processes. Diosmetin (DT), the active metabolite of diosmin, a widely used venoactive drug, has emerged as a potential anticancer agent. Building on our previous findings demonstrating that DT enhances doxorubicin efficacy, this study investigated its effects on tumor cell plasticity and stromal activation-associated responses. EMT was induced in MCF-7 cells, while a stromal model was established by TGF-β-mediated activation of BJ fibroblasts toward a cancer-associated fibroblast (CAF)-like phenotype. Additionally, doxorubicin-induced senescence was generated in fibroblasts. Migration assays and quantitative real-time PCR were used to assess functional and transcriptional changes. EMT induction resulted in decreased CDH1 expression and increased levels of VIM, MMP2, MMP9, IL-6, and HIF-1A, accompanied by enhanced migratory activity. DT attenuated TGF-β-induced CAF-like activation, as reflected by reduced expression of ACTA2, HGF, MMP2, MMP9, and IL6, and modulated hyaluronan turnover-related genes. Moreover, DT partially alleviated selected senescence-associated features in doxorubicin-treated fibroblasts. Collectively, these findings indicate that DT modulates EMT-associated plasticity and stromal activation-related responses in parallel in vitro models. Given its origin as a metabolite of a clinically used compound and its previously demonstrated chemosensitizing properties, DT may warrant further investigation as a potential adjunctive agent to modulate tumor- and stromal-associated processes in breast cancer.