Synergistic Antitumor Potential of Propolis With 6‑Mercaptopurine and 5‑Fluorouracil

6-MP and 5-FU are effective anticancer drugs; still, their efficacy is limited by inadequate solubility and dose-dependent toxicity. Propolis, high in bioactive chemicals, was investigated for its synergistic effects to improve efficacy. GC-MS analysis found 20 bioactive chemicals that were docked against cyclin-dependent kinase 2 and aromatase. Compounds 1,3-dipalmitin and rac-1-oleoyl-3-linoleoylglycerol demonstrated the highest affinities (- 10.93 to -13.18 kcal/mol), indicating possible inhibition of cell cycle and estrogen biosynthesis regulators. Co-treatment with propolis and chemotherapeutic exhibited a marked reduction of IC₅₀ values in both MCF-7 and HepG2 cells, with the most significant reduction for the 5-FU-propolis combination (IC₅₀ of 12.0 µg/mL) compared with 5-FU alone (26.2 µg/mL in MCF-7 and 15.8 µg/mL in HepG2). The Chou-Talalay analysis confirmed synergy (CI < 1), for 5 FU with propolis (CI = 0.46 in MCF 7). Combination therapy elicited S-phase arrest, also impairing mitochondrial membrane potential and altering the path of cell death toward necrosis and late-stage apoptosis. Propolis serves as a prospective chemotherapeutic adjuvant that enhances the anticancer efficacy of 6-MP and 5-FU, allowing dose reduction, minimizing toxicity, and potentially overcoming drug resistance in breast cancer treatment. However, the therapeutic use of this synergistic technique requires confirmation via pharmacokinetic profiling, extensive vivo research, and considered clinical trials.