{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:10:15Z","timestamp":1753891815529,"version":"3.41.2"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T00:00:00Z","timestamp":1683676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010249","name":"School of Medicine, Indiana University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010249","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Gastric adenocarcinoma (GAC) is the fourth leading cause of cancer death worldwide. Systemic chemotherapy is a preferred treatment option for advanced and recurrent GAC, but response rates and survival prolongation remain limited. Tumor angiogenesis plays a critical role in GAC growth, invasion and metastasis. We investigated the antitumor efficacy of nintedanib, a potent triple angiokinase inhibitor for VEGFR-1\/2\/3, PDGFR-\u03b1\/\u03b2 and FGFR-1\/2\/3, alone or in combination with chemotherapy, in preclinical models of GAC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Animal survival studies were performed in peritoneal dissemination xenografts in NOD\/SCID mice using human GAC cell lines MKN-45 and KATO-III. Tumor growth inhibition studies were performed in subcutaneous xenografts in NOD\/SCID mice using human GAC cell lines MKN-45 and SNU-5. The mechanistic evaluation involved Immunohistochemistry analyses in tumor tissues obtained from subcutaneous xenografts. <jats:italic>In vitro<\/jats:italic> cell viability assays were performed using a colorimetric WST-1 reagent.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In MKN-45 GAC cell-derived peritoneal dissemination xenografts, animal survival was improved by nintedanib (33%), docetaxel (100%) and irinotecan (181%), while oxaliplatin, 5-FU and epirubicin had no effect. The addition of nintedanib to docetaxel (157%) or irinotecan (214%) led to a further extension in animal survival. In KATO-III GAC cell-derived xenografts carrying <jats:italic>FGFR2<\/jats:italic> gene amplification, nintedanib extended survival by 209%. Again, the addition of nintedanib further enhanced the animal survival benefits of docetaxel (273%) and irinotecan (332%). In MKN-45 subcutaneous xenografts, nintedanib, epirubicin, docetaxel and irinotecan reduced tumor growth (range: 68-87%), while 5-FU and oxaliplatin had a smaller effect (40%). Nintedanib addition to all chemotherapeutics demonstrated a further reduction in tumor growth. Subcutaneous tumor analysis revealed that nintedanib attenuated tumor cell proliferation, reduced tumor vasculature and increased tumor cell death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Nintedanib showed notable antitumor efficacy and significantly improved taxane or irinotecan chemotherapy responses. These findings indicate that nintedanib, alone and in combination with a taxane or irinotecan, has the potential for improving clinical GAC therapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2023.1145999","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T19:10:20Z","timestamp":1683745820000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Enhancing gastric cancer conventional chemotherapy effects by triple angiokinase inhibitor nintedanib in preclinical models"],"prefix":"10.3389","volume":"13","author":[{"given":"Niranjan","family":"Awasthi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret 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