Antihistamine drug terfenadine suppressed the cycle progression of gastric cancer cells by targeting PI3K/AKT/mTOR signaling.

[BACKGROUND] Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, highlighting the urgent need for effective and accessible therapies. Drug repurposing offers a cost-effective strategy to identify novel candidates from approved drugs. Terfenadine, a classical antihistamine with an established safety profile, has demonstrated antitumor activity in various malignancies; however, its efficacy and mechanism in GC have not been systematically explored. This study investigates the therapeutic potential of terfenadine in GC and elucidates its underlying molecular mechanisms.

[METHODS] Cytotoxicity was assessed in AGS, HGC27, and MKN45 GC cell lines. Effects on proliferation, colony formation, migration, apoptosis, cell cycle distribution, and mitochondrial membrane potential were examined. Mechanisms were explored through bioinformatics analysis, molecular docking, and Western blotting. Synergy with 5-fluorouracil (5-Fu) was evaluated using checkerboard assays and analyzed by SynergyFinder. efficacy was validated in a patient-derived xenograft (PDX) model.

[RESULTS] Terfenadine exhibited potent cytotoxicity against GC cells, with IC values of 5.14 μM (AGS), 3.95 μM (HGC27), and 5.01 μM (MKN45) at 48 h, demonstrating superior potency compared to 5-Fu in AGS and HGC27 cells. It significantly suppressed colony formation and migration, induced G0/G1 phase arrest downregulation of CDK4/6 and phosphorylated Rb, and promoted mitochondrial apoptosis as evidenced by nuclear condensation and loss of mitochondrial membrane potential. Molecular docking predicted strong binding affinity to AKT (score: 9.09). Western blot analysis revealed that terfenadine treatment reduced the expression of PI3K, total and phosphorylated AKT, and mTOR, indicating modulation of the PI3K/AKT/mTOR pathway. Combination with 5-Fu produced synergistic cytotoxicity (synergy scores >10 b y Loewe and HSA models). In the PDX model, terfenadine (10 mg/kg) significantly suppressed tumor growth, reducing final tumor weight by 41.2% ( < 0.001).

[CONCLUSION] This study demonstrates that terfenadine exerts multifaceted antitumor effects in GC through modulation of the PI3K/AKT/mTOR pathway, exhibits synergistic activity with 5-Fu, and shows efficacy in a clinically relevant PDX model. These findings support the repurposing of terfenadine as a promising therapeutic agent for GC.