Strategies to improve anticancer potential of natural substances

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, as it lacks estrogen, progesterone, and HER2 receptors. This absence renders targeted therapies directed against these receptors ineffective, making chemotherapy the only available systemic treatment—with doxorubicin being one of the most widely used agents. However, its non-specific cytotoxicity, combined with the frequent development of drug resistance, creates an urgent need to develop new therapeutic strategies for TNBC treatment. This study proposes a combined therapy using a nutraceutical with reported antitumoral properties, garcinol, together with doxorubicin, delivered via a graphene quantum dot (GQD) nanocarrier system. In vitro experiments using MDA-MB-231 cells showed that garcinol significantly reduced cell viability when combined with doxorubicin, thereby enhancing the cytotoxic effect of chemotherapy. The combination induced apoptosis, as evidenced by increased caspase-3 activation and PARP cleavage, and suppressed pro-survival signaling pathways including NF-κB, p-ERK, and Cyclin D1. Transcriptomic analysis revealed that the GQD-conjugated therapy modulated the expression of key genes involved in cancer-related pathways, downregulating several oncogenes (CDK4, AURKB, HDAC1, FZR1, TRIP13) and upregulating the tumor suppressor CDKN1C. Notably, this effect was observed in both wild-type and doxorubicin-resistant MDA-MB-231 cells. These findings suggest that garcinol and the GQD delivery system can effectively support doxorubicin therapy by enhancing its efficacy and counteracting resistance mechanisms, ultimately representing a safer and more personalized treatment option for patients with TNBC.