Water-based propolis enhances 5-fluorouracil drug efficiency in gastric and colorectal cancer cells through cell stress response, anti-migratory, and apoptotic effects regardless of p53 status.

Digestive system tumors, including gastric and colorectal cancers, have notable global incidence and mortality rates. While 5-Fluorouracil (5-FU) is widely used in treating gastrointestinal (GI) cancers, resistance often limits its effectiveness. Recent research has focused on the potential of natural products, such as propolis, a resin produced by honeybees, as adjuncts in cancer therapy. This study examined whether water-based propolis (WBP) could enhance the therapeutic effects of 5-FU on AGS (p53-wild-type) and Caco-2 (p53-null) cancer cell lines, aiming to propose a new combined treatment strategy. The findings demonstrated that WBP and 5-FU exhibited dose- and time-dependent cytotoxicity, with WBP increasing the therapeutic efficiency of 5-FU by reducing its half-maximal inhibitory concentration in both cancer cell lines, and reducing 5-FU toxicity in non-cancerous cells. Notably, cancer cells expressing p53 showed greater sensitivity to 5-FU; however, WBP demonstrated similar effects in both cell lines. The combined therapy of WBP (100 µg/mL for 48-h) and 5-FU (10 µg/mL for 48-h) with synergistic effects significantly reduced cell proliferation and motility. Moreover, combined treatments caused increased reactive oxygen species production, collapse of mitochondrial membrane potential, endoplasmic reticulum stress, and autophagy, thus leading to cell cycle arrest and apoptosis compared to individual treatments and controls, regardless of p53 expression in both cancer cells. These findings suggest that WBP, a natural product, could supplement 5-FU chemotherapy by enhancing its antitumor effectiveness, warranting further investigation for treating GI cancers.