{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T22:15:27Z","timestamp":1788387327046,"version":"build-2803163510"},"reference-count":23,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Endometrial carcinoma is among the most common gynecological malignancies, with recurrence and chemoresistance remaining major clinical challenges. This study aimed to evaluate the combined effects of Boswellic acid (BA), a natural pentacyclic triterpene, and Gemcitabine (GEM), a nucleoside analog chemotherapeutic, on hypoxia, angiogenesis, and apoptosis in human endometrial cancer cells. Materials and Methods: ECC-1 cells were treated with BA, GEM, or their combination under normoxic and hypoxic conditions. Cell viability (MTT assay); nuclear morphology (NucBlue staining); cell cycle distribution (PI flow cytometry); angiogenesis (VEGF ELISA expression); apoptosis (Caspase-3\/7 activity; Bax; Bcl-2 expression); inflammatory cytokines (IL-1\u03b2; IL-6; TNF-\u03b1); and gene ontology enrichment were analyzed. Results: Both BA and GEM reduced cell viability in a dose- and time-dependent manner, with the combination producing synergistic cytotoxicity and lower IC50 values. Hypoxia enhanced drug sensitivity, particularly in combination therapy. BA and GEM significantly suppressed HIF-1\u03b1 and VEGF expression, with maximal inhibition observed in the combination group. Apoptotic induction was confirmed by increased Bax and Caspase-3 and decreased Bcl-2 expression, together with elevated Caspase-3\/7, -8, and -9 activity. Pro-inflammatory cytokine levels were markedly reduced, and gene ontology analysis revealed enrichment of apoptotic, anti-proliferative, and anti-angiogenic pathways. Conclusions: BA + GEM combination synergistically suppresses hypoxia-driven angiogenesis and promotes apoptosis in endometrial cancer cells. These findings support its potential as an adjuvant therapeutic approach, warranting further preclinical and clinical validation.<\/jats:p>","DOI":"10.3390\/medicina61122181","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T14:52:24Z","timestamp":1765205544000},"page":"2181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Boswellic Acid Enhances Gemcitabine\u2019s Inhibition of Hypoxia-Driven Angiogenesis in Human Endometrial Cancer"],"prefix":"10.3390","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8286-2824","authenticated-orcid":false,"given":"Senem","family":"Alkan Akal\u0131n","sequence":"first","affiliation":[{"name":"Division of Gynecology and Obstetrics, Private Medical Practice, Bursa 16990, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasemin","family":"Af\u015fin","sequence":"additional","affiliation":[{"name":"Gynecology and Obstetrics, Private Batman Life Hospital, Batman 72040, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9957-0211","authenticated-orcid":false,"given":"\u0130lhan","family":"\u00d6zdemir","sequence":"additional","affiliation":[{"name":"Department of Histology Embryology, Faculty of Medicine, Kahramanmara\u015f S\u00fct\u00e7\u00fc \u0130mam University, Kahramanmara\u015f 46100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7317-5467","authenticated-orcid":false,"given":"Mehmet Cudi","family":"Tuncer","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Dicle University, Diyarbak\u0131r 21280, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9435-8139","authenticated-orcid":false,"given":"\u015eamil","family":"\u00d6zt\u00fcrk","sequence":"additional","affiliation":[{"name":"Vocational School of Health Services, \u00c7anakkale Onsekiz Mart University, \u00c7anakkale 17100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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