{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:14:59Z","timestamp":1793146499707,"version":"4.5.0"},"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172580"],"award-info":[{"award-number":["82172580"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Xi'an No. 9 Hospital Fund","award":["2022yb11"],"award-info":[{"award-number":["2022yb11"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>5-Fluorouracil (5-FU) is widely used in the treatment of gastric cancer, and the emergence of drug resistance and toxic effects has limited its application. Therefore, there is an urgent need for safe and effective novel drugs or new therapies. \u03b2-Ionone (BI) is found in vegetables and fruits and possesses an inhibitory proliferation of tumor cells in vitro and in vivo. In this study, we investigated whether BI could enhance the inhibitory effects of 5-FU on the proliferation of gastric adenocarcinoma cells and the growth of gastric cancer cell xenografts in a mouse model. The effects of BI and 5-FU alone or their combination on the cell viability, apoptosis, and mitochondrial membrane potential, the cell cycle, and its related proteins\u2014Cyclin D1, and CDK4 as well as PCNA and GSK-3\u03b2 were evaluated in SGC-7901 cells and MKN45 cells by MTT, MB, flow cytometry and Western blot. In addition, the effects of BI and 5-FU alone or their combination on the growth of SGC-7901 cell xenografts in nude mice were investigated. The results showed that BI significantly enhanced the sensitivity of gastric adenocarcinoma cells to 5-FU in vitro and in vivo, i.e. proliferation inhibited, apoptosis induced and GSK-3\u03b2 protein activated. Therefore, our results suggest that BI increases the antitumor effect of 5-FU on gastric adenocarcinoma cells, at least partly from an activated GSK-3\u03b2 signaling pathway.<\/jats:p>","DOI":"10.1371\/journal.pone.0309014","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T18:10:06Z","timestamp":1725646206000},"page":"e0309014","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["\u03b2-Ionone enhances the inhibitory effects of 5-fluorouracil on the proliferation of gastric adenocarcinoma cells by the GSK-3\u03b2 signaling pathway"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9103-588X","authenticated-orcid":true,"given":"Fa-lin","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6653-0053","authenticated-orcid":true,"given":"Jiaren","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,9,6]]},"reference":[{"issue":"8","key":"pone.0309014.ref001","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1002\/ijc.31937","article-title":"Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods","volume":"144","author":"J Ferlay","year":"2019","journal-title":"Int J Cancer"},{"issue":"3","key":"pone.0309014.ref002","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"H Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"issue":"6","key":"pone.0309014.ref003","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1097\/MOG.0b013e32833efd9b","article-title":"Multidisciplinary management of gastric cancer","volume":"26","author":"Y Jiang","year":"2010","journal-title":"Curr Opin Gastroenterol"},{"issue":"11","key":"pone.0309014.ref004","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1093\/annonc\/mdh422","article-title":"Palliative chemotherapy for advanced gastric cancer","volume":"15","author":"SS W\u00f6hrer","year":"2004","journal-title":"Ann Oncol"},{"issue":"11","key":"pone.0309014.ref005","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/nrd3216","article-title":"Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements","volume":"9","author":"S Kummar","year":"2010","journal-title":"Nat Rev Drug Discov"},{"issue":"12 Suppl","key":"pone.0309014.ref006","first-page":"3479s","article-title":"Potential synergy of phytochemicals in cancer prevention: mechanism of action","volume":"134","author":"RH Liu","year":"2004","journal-title":"J Nutr"},{"issue":"8","key":"pone.0309014.ref007","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.2174\/1871520615666150302125707","article-title":"Cancer chemoprevention by natural carotenoids as an efficient strategy","volume":"15","author":"A. 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Balbi","year":"2006","journal-title":"Bioorg Med Chem"},{"issue":"20","key":"pone.0309014.ref030","doi-asserted-by":"crossref","first-page":"6343","DOI":"10.1016\/j.bmcl.2012.08.084","article-title":"Synthesis of \u03b2-ionone derived chalcones as potent antimicrobial agents","volume":"22","author":"V Sharma","year":"2012","journal-title":"Bioorg Med Chem Lett"},{"issue":"4","key":"pone.0309014.ref031","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1080\/01635581.2013.776091","article-title":"\u03b2-ionone induces cell cycle arrest and apoptosis in human prostate tumor cells","volume":"65","author":"S Jones","year":"2013","journal-title":"Nutr Cancer"},{"issue":"3","key":"pone.0309014.ref032","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1046\/j.1365-2184.2003.00266.x","article-title":"The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer","volume":"36","author":"K Vermeulen","year":"2003","journal-title":"Cell 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PCNA-interacting proteins for phosphorylation","volume":"275","author":"S Koundrioukoff","year":"2000","journal-title":"J Biol Chem"},{"issue":"12","key":"pone.0309014.ref036","doi-asserted-by":"crossref","DOI":"10.3390\/ijms17122144","article-title":"Apoptosis in Cellular Society: Communication between Apoptotic Cells and Their Neighbors","volume":"17","author":"Y Kawamoto","year":"2016","journal-title":"Int J Mol Sci"},{"key":"pone.0309014.ref037","doi-asserted-by":"crossref","first-page":"101239","DOI":"10.1016\/j.redox.2019.101239","article-title":"Programmed necrotic cell death of macrophages: Focus on pyroptosis, necroptosis, and parthanatos","volume":"26","author":"N Robinson","year":"2019","journal-title":"Redox Biol"},{"issue":"8","key":"pone.0309014.ref038","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1007\/s00262-011-1008-4","article-title":"Targeting the extrinsic apoptosis signaling pathway for cancer therapy","volume":"60","author":"TJ Sayers","year":"2011","journal-title":"Cancer Immunol Immunother"},{"issue":"7","key":"pone.0309014.ref039","doi-asserted-by":"crossref","first-page":"569","DOI":"10.2174\/1568009043332763","article-title":"Targeting apoptosis pathways in cancer therapy","volume":"4","author":"S Fulda","year":"2004","journal-title":"Curr Cancer Drug Targets"},{"key":"pone.0309014.ref040","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1186\/1471-2407-12-409","article-title":"Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis","volume":"12","author":"A Goc","year":"2012","journal-title":"BMC Cancer"},{"issue":"Suppl 2","key":"pone.0309014.ref041","doi-asserted-by":"crossref","first-page":"S131","DOI":"10.33549\/physiolres.934345","article-title":"The PI3k\/Akt pathway is associated with angiogenesis, oxidative stress and survival of mesenchymal stem cells in pathophysiologic condition in ischemia","volume":"68","author":"A Samakova","year":"2019","journal-title":"Physiol Res"},{"issue":"2","key":"pone.0309014.ref042","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1124\/jpet.110.174870","article-title":"Anticancer efficacy of simvastatin on prostate cancer cells and tumor xenografts is associated with inhibition of Akt and reduced prostate-specific antigen expression","volume":"336","author":"ST Kochuparambil","year":"2011","journal-title":"J Pharmacol Exp Ther"},{"key":"pone.0309014.ref043","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/1471-2407-11-109","article-title":"P27(Kip1), regulated by glycogen synthase kinase-3\u03b2, results in HMBA-induced differentiation of human gastric cancer cells","volume":"11","author":"M Wei","year":"2011","journal-title":"BMC Cancer"},{"issue":"10","key":"pone.0309014.ref044","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/35096075","article-title":"The renaissance of GSK3","volume":"2","author":"P Cohen","year":"2001","journal-title":"Nat Rev Mol Cell Biol"},{"key":"pone.0309014.ref045","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1042\/bj2960015","article-title":"Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling","volume":"296","author":"C Sutherland","year":"1993","journal-title":"Biochem J"},{"issue":"42","key":"pone.0309014.ref046","doi-asserted-by":"crossref","first-page":"32649","DOI":"10.1074\/jbc.M000643200","article-title":"The integrin-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3beta and cAMP-responsive element-binding protein-dependent pathways","volume":"275","author":"M D\u2019Amico","year":"2000","journal-title":"J Biol Chem"},{"issue":"6","key":"pone.0309014.ref047","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S1368-8375(01)00121-X","article-title":"Expression of cyclin D1 and GSK-3beta and their predictive value of prognosis in squamous cell carcinomas of the tongue","volume":"38","author":"H Goto","year":"2002","journal-title":"Oral Oncol"},{"issue":"3","key":"pone.0309014.ref048","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1093\/carcin\/24.3.435","article-title":"Cyclin D1 over-expression correlates with beta-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3 beta and ERK1\/2 in mouse hepatic carcinogenesis","volume":"24","author":"J Gotoh","year":"2003","journal-title":"Carcinogenesis"},{"key":"pone.0309014.ref049","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1471-2121-7-33","article-title":"Glycogen synthase kinase 3 has a limited role in cell cycle regulation of cyclin D1 levels","volume":"7","author":"K Yang","year":"2006","journal-title":"BMC Cell Biol"}],"container-title":["PLOS 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