{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:11:18Z","timestamp":1789996278026,"version":"4.0.1"},"reference-count":55,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016624","name":"Applied Science Private University","doi-asserted-by":"publisher","award":["DRGS-2015-2016-35"],"award-info":[{"award-number":["DRGS-2015-2016-35"]}],"id":[{"id":"10.13039\/100016624","id-type":"DOI","asserted-by":"publisher"}]},{"award":["DRGS-2015-2016-35"],"award-info":[{"award-number":["DRGS-2015-2016-35"]}],"id":[{"id":"https:\/\/ror.org\/01ah6nb52","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Cisplatin resistance remains a significant challenge in the effective treatment of breast cancer, underscoring the need for novel combination-based therapeutic strategies. Background: This study investigated the anticancer effects of ellagic acid (EA) and metformin (MET), both individually and in combination, against parental and cisplatin-resistant breast cancer models. To our knowledge, this is the first study to evaluate the EA-MET combination in the context of cisplatin resistance in breast cancer. Methods: The in vitro antiproliferative and apoptotic effects of EA and MET were assessed using MTT and caspase-3 assays in parental (EMT-6\/P) and cisplatin-resistant (EMT-6\/CPR) cells. An in vivo study was also conducted to evaluate the anti-tumor effects of the treatment combinations in mice bearing EMT-6\/P or EMT-6\/CPR tumors. Liver enzymes and creatinine levels were measured to assess potential hepatic and renal toxicity. Results: In vitro combination index analysis indicated a synergistic interaction between EA and MET in EMT-6\/P cells (CI = 0.45) and a strong synergistic interaction in EMT-6\/CPR cells (CI = 0.29) under the tested conditions. In vivo, the addition of the combination to cisplatin resulted in significant tumor size reductions of 73.83% and 56.25% in EMT-6\/P and EMT-6\/CPR bearing mice, respectively, along with tumor regressions of 66.6% and 50%, respectively. Conclusions: Thecombination of metformin and ellagic acid shows promise as a potential treatment for cisplatin-resistant breast cancer. Further research is needed to elucidate the precise anticancer mechanisms underlying this combination.<\/jats:p>","DOI":"10.3390\/nu18183047","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:50:03Z","timestamp":1789995003000},"page":"3047","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ellagic Acid and Metformin: In Vitro Synergy and Enhanced Cisplatin Efficacy In Vivo in Resistant Breast Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1738-0102","authenticated-orcid":false,"given":"Balqis","family":"Jdaitawi","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Applied Science Private University, Amman 11937, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Moudi M.","family":"Alasmari","sequence":"additional","affiliation":[{"name":"College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Jeddah 11481, Saudi Arabia"},{"name":"King Abdullah International Medical Research Centre (KAIMRC), Jeddah 11481, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1960-0092","authenticated-orcid":false,"given":"Heba K.","family":"Alshaeri","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Rabigh 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5978-6779","authenticated-orcid":false,"given":"Doaa Omar","family":"Anbarserry","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Rabigh 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1907-120X","authenticated-orcid":false,"given":"Alexandra","family":"Makai","sequence":"additional","affiliation":[{"name":"Institute of Physiotherapy and Sports Science, Faculty of Health Sciences, University of P\u00e9cs, H-7621 P\u00e9cs, Hungary"},{"name":"Physical Activity Research Group, J\u00e1nos Szent\u00e1gothai Research Center, University of P\u00e9cs, H-7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Hadeel Shaher","family":"Al Junaidi","sequence":"additional","affiliation":[{"name":"Faculty of Allied Medical Sciences, Applied Science Private University, Amman 11937, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1942-8982","authenticated-orcid":false,"given":"Wamidh H.","family":"Talib","sequence":"additional","affiliation":[{"name":"Faculty of Allied Medical Sciences, Applied Science Private University, Amman 11937, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6068-6858","authenticated-orcid":false,"given":"M\u00e1rta","family":"Hock","sequence":"additional","affiliation":[{"name":"Institute of Physiotherapy and Sports Science, Faculty of Health Sciences, University of P\u00e9cs, H-7621 P\u00e9cs, Hungary"},{"name":"Physical Activity Research Group, J\u00e1nos Szent\u00e1gothai Research Center, University of P\u00e9cs, H-7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","first-page":"e70090","article-title":"Global cancer statistics 2024: GLOBOCAN estimates of incidence and mortality worldwide for 34 cancers in 186 countries","volume":"76","author":"Sung","year":"2026","journal-title":"CA Cancer J. 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