{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T04:59:51Z","timestamp":1781067591077,"version":"3.54.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Metformin (MET), a widely used antidiabetic agent, and parthenolide (PAR), a natural compound recognized for its anti-inflammatory properties, have both been extensively explored for their anticancer potential. The present study aimed to investigate the anticancer activity of their combination against breast cancer\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The antiproliferative effects of MET, PAR, and their combination were evaluated against a panel of breast cancer cell lines (EMT6\/P, MDA-MB-231, and T47D) using the MTT assay. Synergistic interactions were assessed using the isobolographic method to calculate the combination index (CI). Apoptosis and angiogenesis were further investigated in T47D cells through caspase-3 activity assays and measurement of vascular endothelial growth factor (VEGF) levels, respectively. For\n                      <jats:italic>in vivo<\/jats:italic>\n                      assessment, EMT6\/P cells were inoculated in BALB\/c mice, and the antitumor effects of MET, PAR, and their combination were evaluated by monitoring tumor size. Treatment-related toxicity was assessed by measuring serum levels of aspartate transaminase (AST), alanine transaminase (ALT), and creatinine.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MET and PAR exhibited a clear synergistic antiproliferative interaction against all tested breast cancer cell lines, with varying degrees of synergism observed.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , combination therapy produced a significant reduction in tumor size, with a cure rate of 50% and zero treatment-related mortality. The combination significantly induced caspase-3-dependent apoptosis and reduced VEGF expression compared to either agent alone. Serum AST, ALT, and creatinine levels in combination-treated tumor-bearing mice remained within normal ranges, supporting the safety of this regimen.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The combination of MET and PAR demonstrates synergistic anticancer activity against breast cancer both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      , acting through apoptosis induction and angiogenesis inhibition. Given these promising findings, further studies are warranted to provide more comprehensive molecular and mechanistic characterization of this combination and to support its future clinical evaluation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1843223","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T04:28:21Z","timestamp":1781065701000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Combination of metformin and parthenolide inhibits breast cancer in mice by apoptosis induction and angiogenesis inhibition"],"prefix":"10.3389","volume":"17","author":[{"given":"Raghad K.","family":"Alomari","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Applied Science Private University","place":["Amman, Jordan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moudi M","family":"Alasmari","sequence":"additional","affiliation":[{"name":"College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)","place":["Jeddah, Saudi Arabia"]},{"name":"King Abdullah International Medical Research Centre (KAIMRC)","place":["Jeddah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba K","family":"Alshaeri","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University","place":["Rabigh, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Makai","sequence":"additional","affiliation":[{"name":"Institute of Physiotherapy and Sports Science, Faculty of Health Sciences, University of P\u00e9cs","place":["P\u00e9cs, Hungary"]},{"name":"Physical Activity Research Group, J\u00e1nos Szent\u00e1gothai Research Center, University of P\u00e9cs","place":["P\u00e9cs, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wamidh H","family":"Talib","sequence":"additional","affiliation":[{"name":"Faculty of Allied Medical Sciences, Applied Science Private University","place":["Amman, Jordan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rta","family":"Hock","sequence":"additional","affiliation":[{"name":"Institute of Physiotherapy and Sports Science, Faculty of Health Sciences, University of P\u00e9cs","place":["P\u00e9cs, Hungary"]},{"name":"Physical Activity Research Group, J\u00e1nos Szent\u00e1gothai Research Center, University of P\u00e9cs","place":["P\u00e9cs, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"B1","unstructured":"Cancer\n          \n          \n          \n          2025"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3322\/CAAC.21834","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 Clin"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/J.BIOPHA.2022.113054","article-title":"Targeting cancer signaling pathways by natural products: Exploring promising anti-cancer agents","volume":"150","author":"Hashem","year":"2022","journal-title":"Biomedicine Pharmacotherapy"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/J.METABOL.2022.155223","article-title":"Metformin: Is it a drug for all reasons and diseases","volume":"133","author":"Triggle","year":"2022","journal-title":"Metabolism"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/J.TIPS.2020.09.001","article-title":"Metformin and systemic metabolism","volume":"41","author":"He","year":"2020","journal-title":"Trends Pharmacol Sci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/J.LFS.2020.117717","article-title":"Anticancer mechanisms of metformin: A review of the current evidence","volume":"254","author":"Zhao","year":"2020","journal-title":"Life Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-017-4372-6","article-title":"Repurposing metformin for the prevention of cancer and cancer recurrence","volume":"60","author":"Heckman-Stoddard","year":"2017"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00191","article-title":"Metformin and its benefits for various diseases","volume":"11","author":"Lv","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B9","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/B978-0-444-64056-7.00003-9","article-title":"The current and potential therapeutic uses of parthenolide","volume":"58","author":"Agatonovic-Kustrin","year":"2018","journal-title":"Stud Nat Prod Chem"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1039\/C9NP00049F","article-title":"Advances in chemistry and bioactivity of parthenolide","volume":"37","author":"Freund","year":"2020","journal-title":"Nat Prod Rep"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/S10753-011-9346-0","article-title":"Parthenolide, a sesquiterpene lactone, expresses multiple anti-cancer and anti-inflammatory activities","volume":"35","author":"Mathema","year":"2012","journal-title":"Inflammation"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-63931-8.00009-6","article-title":"Parthenolide and parthenolide-like sesquiterpene lactones as multiple targets drugs: Current knowledge and new developments","volume":"52","author":"Seca","year":"2017","journal-title":"Stud Nat Prod Chem"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/APP10093001","article-title":"Applications of sesquiterpene lactones: A review of some potential success cases","volume":"10","author":"Moujir","year":"2020","journal-title":"Appl Sci"},{"key":"B14","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1016\/J.DRUDIS.2013.05.005","article-title":"Parthenolide: From plant shoots\u00a0to\u00a0cancer roots","volume":"18","author":"Ghantous","year":"2013","journal-title":"Drug Discov Today"},{"key":"B15","doi-asserted-by":"publisher","first-page":"38022","DOI":"10.18632\/ONCOTARGET.16723","article-title":"Combination therapy in combating cancer","volume":"8","author":"Mokhtari","year":"2017","journal-title":"Oncotarget"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.2174\/1381612825666190110162529","article-title":"Anticancer hybrid combinations: Mechanisms of action, implications and future perspectives","volume":"24","author":"Dom\u00ednguez-Mart\u00edn","year":"2018","journal-title":"Curr Pharm Des"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.708943","article-title":"Editorial: Novel combination therapies for the treatment of solid cancers","volume":"11","author":"Ayoub","year":"2021","journal-title":"Front Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/S40880-017-0184-9","article-title":"Metformin targets multiple signaling pathways in cancer","volume":"36","author":"Lei","year":"2017","journal-title":"Chin J Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1177\/1758834016687482","article-title":"Combination of metformin and curcumin targets breast cancer in mice by angiogenesis inhibition, immune system modulation and induction of p53 independent apoptosis","volume":"9","author":"Falah","year":"2017","journal-title":"Ther Adv Med Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.4161\/cc.8.6.7933","article-title":"Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro","volume":"8","author":"Alimova","year":"2009","journal-title":"Cell Cycle"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3109\/13880209.2014.911919","article-title":"Effect of parthenolide on growth and apoptosis regulatory genes of human cancer cell lines","volume":"53","author":"Al-Fatlawi","year":"2015","journal-title":"Pharm Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/J.APJTM.2017.03.026","article-title":"Antitumor effect of thymoquinone combined with resveratrol on mice transplanted with breast cancer","volume":"10","author":"Alobaedi","year":"2017","journal-title":"Asian Pac J Trop Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-1558","article-title":"Enhancement of docetaxel anti-cancer activity by a novel diindolylmethane (DIM) compound in human non-small cell lung cancer","volume":"15","author":"Ichite","year":"2009","journal-title":"Clin Cancer Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/LABAN.254","article-title":"Estimation of rat mammary tumor volume using caliper and ultrasonography measurements","volume":"42","author":"Faustino-Rocha","year":"2013","journal-title":"Lab Anim (NY)"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0108444","article-title":"Mechanisms by which low glucose enhances the cytotoxicity of metformin to cancer cells both in vitro and in vivo","volume":"9","author":"Zhuang","year":"2014","journal-title":"PLoS One"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1667\/RR14710.1","article-title":"Parthenolide selectively sensitizes prostate tumor tissue to radiotherapy while protecting healthy tissues in vivo","volume":"187","author":"Morel","year":"2017","journal-title":"Radiat Res"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1200\/JCO.2016.69.7722","article-title":"Impact of diabetes, insulin, and metformin use on the outcome of patients with human epidermal growth factor receptor 2\u2013positive primary breast cancer: Analysis from the ALTTO phase III randomized trial","volume":"35","author":"Sonnenblick","year":"2017","journal-title":"J Clin Oncol"},{"key":"B28","unstructured":"The cytotoxic test of metformin hydrochloride to T47D breast cancer cell\n          \n          \n            \n              Rangkuti\n              IY\n            \n            \n              Anjelisa\n              P\n            \n            \n              Hasibuan\n              Z\n            \n          \n          \n          2018"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1055\/a-0631-8046","article-title":"Synergistic anti-proliferative effects of metformin and silibinin combination on T47D breast cancer cells via hTERT and cyclin D1 inhibition","volume":"68","author":"Chatran","year":"2018","journal-title":"Drug Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"e000164","DOI":"10.32892\/jmri.164","article-title":"Metformin inhibits growth of breast cancer cell T47D through decreasing expression of protein P53, BCL2 and cyclin D1","volume":"3","author":"Rangkuti","year":"2019","journal-title":"J Med Res Innov"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/cddiscovery.2017.78","article-title":"Parthenolide prevents resistance of MDA-MB231 cells to doxorubicin and mitoxantrone: The role of Nrf2","volume":"3","author":"Carlisi","year":"2017","journal-title":"Cell Death Discov"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.415","article-title":"Parthenolide generates reactive oxygen species and autophagy in MDA-MB231 cells. A soluble parthenolide analogue inhibits tumour growth and metastasis in a xenograft model of breast cancer","volume":"4","author":"D\u2019Anneo","year":"2013","journal-title":"Cell Death Dis"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4161\/cc.9.1.10407","article-title":"Metformin extends life span of HER-2\/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo","volume":"9","author":"Anisimov","year":"2010","journal-title":"Cell Cycle"},{"key":"B34","doi-asserted-by":"publisher","first-page":"193","DOI":"10.3727\/096504015X14348950540999","article-title":"Combined use of metformin and everolimus is synergistic in the treatment of breast cancer cells","volume":"22","author":"Wang","year":"2015","journal-title":"Oncol Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2024.101946","article-title":"Synergistic anticancer effects of doxorubicin and metformin combination therapy: A systematic review","volume":"45","author":"Jalali","year":"2024","journal-title":"Transl Oncol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-010-0763-9","article-title":"Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells","volume":"123","author":"Zakikhani","year":"2010","journal-title":"Breast Cancer Res Treat"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/ijms262010243","article-title":"Combined XPO1 inhibition and parthenolide treatment can be efficacious in treating triple-negative breast cancer","volume":"26","author":"Paulson","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-020-05649-3","article-title":"Anticancer and apoptotic activities of parthenolide in combination with epirubicin in mda-mb-468 breast cancer cells","volume":"47","author":"Ghorbani-Abdi-Saedabad","year":"2020","journal-title":"Mol Biol Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/ph13080194","article-title":"Parthenolide as cooperating agent for anti-cancer treatment of various Malignancies","volume":"13","author":"Sztiller-Sikorska","year":"2020","journal-title":"Pharmaceuticals"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.03.114","article-title":"The T47D cell line is an ideal experimental model to elucidate the progesterone-specific effects of a luminal A subtype of breast cancer","volume":"486","author":"Yu","year":"2017","journal-title":"Biochem Biophys Res Commun"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17071102","article-title":"Molecular subtypes and mechanisms of breast cancer: Precision medicine approaches for targeted therapies","volume":"17","author":"Carvalho","year":"2025","journal-title":"Cancers"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19123999","article-title":"Caspase-3 mediated cell death in the normal development of the mammalian cerebellum","volume":"19","author":"Lossi","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B43","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.tiv.2017.11.001","article-title":"Metformin and epothilone A treatment up regulate pro-apoptotic PARP-1, Casp-3 and H2AX genes and decrease of AKT kinase level to control cell death of human hepatocellular carcinoma and ovary adenocarcinoma cells","volume":"47","author":"Rogalska","year":"2018","journal-title":"Toxicol Vitro"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2020.1743911","article-title":"Metformin activates AMPK\/SIRT1\/NF-\u03baB pathway and induces mitochondrial dysfunction to drive caspase3\/GSDME-mediated cancer cell pyroptosis","volume":"19","author":"Zheng","year":"2020","journal-title":"Cell Cycle"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.7314\/APJCP.2014.15.12.4897","article-title":"Parthenolide-induced apoptosis, autophagy and suppression of proliferation in HepG2 cells","volume":"15","author":"Sun","year":"2014","journal-title":"Asian Pac J Cancer Prev"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.2147\/DDDT.S355059","article-title":"The emerging potential of parthenolide nanoformulations in tumor therapy","volume":"16","author":"An","year":"2022","journal-title":"Drug Des Devel Ther"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2018.04.045","article-title":"Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF\/PI3K\/Akt signaling pathway","volume":"664","author":"Sun","year":"2018","journal-title":"Gene"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2014.1669","article-title":"Parthenolide exerts inhibitory effects on angiogenesis through the downregulation of VEGF\/VEGFRs in colorectal cancer","volume":"33","author":"Kim","year":"2014","journal-title":"Int J Mol Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/J.PHRS.2016.10.006","article-title":"Metformin: An anti-diabetic drug to fight cancer","volume":"113","author":"Daugan","year":"2016","journal-title":"Pharmacol Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1186\/S13046-019-1211-2","article-title":"Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation","volume":"38","author":"Wang","year":"2019","journal-title":"J Exp Clin Cancer Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1843223\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T04:28:25Z","timestamp":1781065705000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1843223\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2026.1843223"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1843223","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,10]]},"article-number":"1843223"}}