Steryl glucosides as a novel chemosensitizer: Enhancing doxorubicin response in estrogen receptor-positive breast cancer

Background Estrogen receptor-positive (ER⁺) breast cancer is the most prevalent breast cancer subtype, and doxorubicin is a key systemic therapeutic drug. However, its use is limited by toxicity and mechanisms of drug resistance. Steryl glucosides are bioactive glycolipids with potential anticancer and immunomodulatory properties, but their role as chemotherapy-sensitizing agents remains undefined. Methods and results Here, we investigated whether a soybean-derived steryl glucoside preparation (SG) enhances doxorubicin activity primarily in the MCF-7 ER⁺ breast cancer model. SG co-treatment increased doxorubicin-associated cytotoxicity and reduced cell viability of MCF-7. Dose-response matrix analysis and exploratory Bliss independence modeling identified concentration-dependent regions of greater-than-expected combined activity, supporting pharmacological potentiation but not definitive synergy. SG co-treatment also increased γ-H2AX-positive nuclei, consistent with enhanced doxorubicin-associated DNA damage signaling. Fluorescence-based extraction analysis showed increased doxorubicin-associated intracellular fluorescence in SG co-treated cells, while ABCB1 qRT-PCR revealed concentration-dependent transcriptional changes. These findings suggest altered intracellular drug exposure or transport-associated responses, although functional efflux activity was not directly assessed. In an ovariectomized, estradiol-supplemented MCF-7 xenograft model, the SG-doxorubicin group showed the lowest mean tumor-growth trajectory, reduced cumulative tumor burden, lower terminal tumor weight, reduced Ki-67 staining, and increased tumor necrosis. However, the longitudinal tumor-volume analysis did not establish unequivocal superiority over doxorubicin monotherapy. Exploratory T47D data indicated weaker responsiveness, suggesting that the effect may be model-dependent. Conclusion This study provides proof-of-concept evidence that SG can enhance doxorubicin-associated antitumor activity mainly in the MCF-7 model. Further studies are required to define functional transport mechanisms, model generalizability, toxicity, and formal dose-sparing potential. Significance This study provides proof-of-concept evidence that a soybean-derived steryl glucoside preparation can enhance doxorubicin-associated cytotoxicity, DNA damage signaling, and antitumor activity primarily in the MCF-7 estrogen receptor-positive breast cancer model. The findings support further investigation of SG as a candidate chemotherapy-sensitizing adjuvant, while highlighting the need for functional transport assays, broader model validation, comprehensive toxicity assessment, and formal dose-sparing studies before translational conclusions can be drawn.