Differential cellular responses of breast cancer and non-tumorigenic mammary epithelial cells to a fullerene-doxorubicin complex

Breast cancer remains a leading cause of cancer-related mortality among women, with triple-negative breast cancer (TNBC) representing a particularly aggressive subtype with limited therapeutic options. Doxorubicin (DOX), a widely used chemotherapeutic, is limited by systemic toxicity and the emergence of chemoresistance, highlighting the need for strategies that enhance tumor selectivity. Here, we evaluate an acid-treated C₆₀-DOX nanocomplex for selective cytotoxicity toward breast cancer cells (MCF7 and MDA-MB-231) while sparing non-tumorigenic cells (MCF10A). Using real-time impedance monitoring, metabolic assays, and caspase-3/7 activity, we show that C₆₀-DOX reduces DOX-induced stress in MCF10A cells but amplifies metabolic disruption and caspase-3/7 activation in cancer cells. Importantly, MDA-MB-231 TNBC cells demonstrated the highest sensitivity increase, with early metabolic impairment, ATP depletion, and enhanced caspase-3/7 activation. Together with previous reports, our findings suggest that redox modulation and mitochondrial perturbation may contribute to the observed cell type-selective response. These results highlight a dual behavior of C₆₀-DOX, integrating metabolic, apoptotic, and impedance readouts to reveal a cell type-dependent cytotoxicity profile. Overall, this study indicates that C₆₀-based nanocarriers may offer a promising strategy for improving the selective cytotoxic profile of DOX in breast cancer cells, particularly aggressive TNBC cells, while reducing DOX-associated toxicity in non-tumorigenic cells.