Anti-Cancer Effect of a New 5-FU Derivative Containing Triazole-Bearing Mannose (5-FUD-MAN) Against Human Breast Cancer Cells Through LC3B-Mediated Cell Death

Breast cancer remains one of the most common malignancies affecting women worldwide. Despite the effectiveness of traditional chemotherapeutic agents such as 5-fluorouracil (5-FU), their lack of selectivity often results in damage to healthy tissues, leading to undesirable adverse effects. The aim of this study was to modify 5-FU with mannose containing 1,2,3-triazole compound to reduce its toxic effect, and to investigate the anticancer properties of the resulting 5-FU derivative (5-FUD-Man) in ER-positive MCF-7 breast cancer cells. Our results demonstrated that while 5-FU caused significant cytotoxicity in both cancerous and healthy cells, 5-FUD-Man showed selective cytotoxicity, with minimal effects on MCF-10A cells. Furthermore, immunofluorescence staining results indicated that 5-FUD-Man was more strongly activated apoptosis (Caspase-3, AIF), autophagy-mediated (LC3B), and stress-associated signaling pathways (ERK1/2) in MCF-7 cells compared to 5-FU. These findings suggest that the combined use of carbohydrate-based targeting via mannose and a bioactive triazole compound may enhance the selectivity and therapeutic efficacy of 5-FU-based treatments in breast cancer. Overall, 5-FUD-Man appears to be a promising candidate for further development as a more targeted and potentially safer therapeutic strategy.