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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.<\/jats:p>","DOI":"10.3390\/ph19091373","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T09:21:19Z","timestamp":1788168079000},"page":"1373","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anticancer Effects of Fluphenazine Alone and in Combination with Cisplatin in Gastric Cancer Cells and a Mouse Xenograft Model"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0040-5428","authenticated-orcid":false,"given":"Seung-Hyeon","family":"Ahn","sequence":"first","affiliation":[{"name":"Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Jihyun","family":"Shin","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Hwayoung","family":"Na","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Hong Kyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Companion Animal Health, College of Biomedical Science & Health, Inje University, Gimhae 50834, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1925-1198","authenticated-orcid":false,"given":"Kyung-Chul","family":"Choi","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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