Synergistic Anticancer Activity of Fucoidan from Lessonia trabeculata Combined with Chemotherapeutic Agents in 4T1 Breast Spheroids

Triple-negative breast cancer (TNBC) is known for being aggressive and potentially resistant to chemotherapy. This means that new ways to improve cancer treatments are a priority. So, the anticancer effect of binary combinations of fucoidan (FuLt) and the chemotherapeutic agents doxorubicin, paclitaxel, and 5-fluorouracil was evaluated. The Chou-Talalay combination index method was used to do this. This method allows the assessment of interactions between products by determining synergism, additive effect and antagonism with combination index <1, =1 and >1, respectively. Synergistic indices (SIs) were selected and applied to 4T1 homotypic spheroids. Oxidative stress caused by SIs was determined after 72 h by measuring the production of ROS and NO in both homotypic and heterotypic spheroids. Three SIs with an inhibitory effect of at least ≥ 0.50 and a dose reduction index > 1 were selected. Considering the experimental and simulated SI, twelve, nineteen, and seven SIs were found for FuLt with doxorubicin, paclitaxel, and 5-fluorouracil, respectively. The highest levels of ROS and NO occurred at 12 and 72 h, respectively, in homotypic and heterotypic spheroids, indicating an immunomodulatory effect in heterotypic spheroids. These results suggest that the synergistic combination of FuLt with chemotherapeutic agents improves drug efficacy and modulates redox dynamics in 4T1 spheroids. Furthermore, FuLt alone exhibits cytotoxic properties.