Anticancer Effects of Fluphenazine Alone and in Combination with Cisplatin in Gastric Cancer Cells and a Mouse Xenograft Model.

Background/Objectives: Gastric cancer remains a leading cause of cancer-related mortality worldwide, highlighting the need for novel therapeutic strategies. Drug repositioning offers a cost-effective approach by identifying new therapeutic applications for clinically approved drugs. Fluphenazine (FPZ), a dopamine receptor D2 antagonist used as an antipsychotic drug, has demonstrated anticancer activity; however, its effects on gastric cancer remain unclear. Methods: This study investigated the anticancer effects of FPZ alone and in combination with cisplatin (DDP) in gastric cancer. Results: In MKN-45 cells, viability was 100%, 101.16%, 61.26%, and 53.12% in the control, FPZ, DDP, and combination groups, respectively; the corresponding values in AGS cells were 100%, 84.95%, 89.94%, and 73.94%. FPZ also inhibited migration and induced apoptosis, while combined treatment increased cytosolic and mitochondrial reactive oxygen species levels and mitochondrial stress. Furthermore, FPZ reduced IL-6 and IL-8 expression and attenuated DDP-induced inflammatory responses. In the mouse xenograft model, the tumor volumes were 1233.65, 1115.75, 768.88, and 309.44 mm3 in the control, FPZ, DDP, and combination groups, respectively. Conclusions: These findings support the potential of FPZ as a repurposed anticancer agent for gastric cancer, particularly in combination with DDP.