{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:28:39Z","timestamp":1785421719472,"version":"3.56.0"},"reference-count":56,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008770","name":"Anadolu University","doi-asserted-by":"crossref","award":["2107S122"],"award-info":[{"award-number":["2107S122"]}],"id":[{"id":"10.13039\/501100008770","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2107S122"],"award-info":[{"award-number":["2107S122"]}],"id":[{"id":"https:\/\/ror.org\/05nz37n09","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>This study investigates the combined effects of cisplatin (CDDP) and \u03b5-viniferin (\u03b5-VNF), a natural stilbenoid, on oxidative stress and apoptosis in HeLa cells. Cytotoxicity was assessed using the MTT assay, and IC50 values were determined as 28 \u00b5M for CDDP and 21 \u00b5M for \u03b5-VNF. Synergistic and antagonistic combination ratios of these doses were tested. Oxidative stress was evaluated via Total Oxidant Status (TOS), Total Antioxidant Status (TAS), Oxidative Stress Index (OSI), Superoxide Dismutase (SOD), Reduced Glutathione (GSH), and Malondialdehyde (MDA). Apoptosis was measured using Annexin V-FITC\/PI staining and caspase-9 activation assays. TAS levels significantly increased in all combination groups compared to the control (control: 266.7 \u00b1 0.1 \u00b5mol\/L; 20% combo: 2466.7 \u00b1 1.0 \u00b5mol\/L). OSI values decreased accordingly (control: 22.5 \u00b1 7.1; 10% combo: 1.6 \u00b1 0.5). GSH levels decreased in the combination groups (e.g., 20%: 0.8 \u00b1 0.2 \u00b5M vs. control: 1.4 \u00b1 0.1 \u00b5M), while MDA levels increased (20%: 3.8 \u00b1 0.5 \u00b5M vs. control: 0.5 \u00b1 0.1 \u00b5M). Caspase-9 positive cells increased markedly (20%: 55.0% vs. control: 13.2%), supporting activation of the mitochondrial apoptotic pathway. Annexin V analysis revealed increased late apoptosis (20%: 76.1%) and early apoptosis (20%: 17.0%).<\/jats:p>","DOI":"10.3390\/molecules31142409","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T15:40:09Z","timestamp":1783525209000},"page":"2409","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cisplatin and \u03b5-Viniferin Synergistically Modulate Oxidative Stress in HeLa Cells: Implications for Redox Modulation in Cervical Cancer Cells"],"prefix":"10.3390","volume":"31","author":[{"given":"Tayyar G\u00f6rkem","family":"Sayer","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2121-971X","authenticated-orcid":false,"given":"Gamze","family":"Y\u0131lmaz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Graduate Education Institute, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filiz","family":"\u00d6zdemir","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.currproblcancer.2018.06.003","article-title":"Cervical cancer worldwide","volume":"42","author":"Vu","year":"2018","journal-title":"Curr. Probl. Cancer"},{"key":"ref_2","first-page":"229","article-title":"A review of cervical cancer: Incidence and disparities","volume":"112","author":"Buskwofie","year":"2020","journal-title":"J. Natl. Med. Assoc."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ali, R., Aouida, M., Alhaj Sulaiman, A., Madhusudan, S., and Ramotar, D. (2022). Can cisplatin therapy be improved? Pathways that can be targeted. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23137241"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"113345","DOI":"10.1016\/j.biopha.2022.113345","article-title":"Cellular landscaping of cisplatin resistance in cervical cancer","volume":"153","author":"Bhattacharjee","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1002\/cncr.30667","article-title":"Cervical cancer: A global health crisis","volume":"123","author":"Small","year":"2017","journal-title":"Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"C849","DOI":"10.1152\/ajpcell.00283.2008","article-title":"Radical-free biology of oxidative stress","volume":"295","author":"Jones","year":"2008","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1089\/ars.2006.8.1865","article-title":"Redefining oxidative stress","volume":"8","author":"Jones","year":"2006","journal-title":"Antioxid. Redox Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1089\/ars.2007.1957","article-title":"Redox regulation of cell survival","volume":"10","author":"Trachootham","year":"2008","journal-title":"Antioxid. Redox Signal."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s00280-003-0726-5","article-title":"Intrinsic oxidative stress in cancer cells: A biochemical basis for therapeutic selectivity","volume":"53","author":"Hileman","year":"2004","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Nosrati, N., Bakovic, M., and Paliyath, G. (2017). Molecular mechanisms and pathways as targets for cancer prevention and progression with dietary compounds. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102050"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1007\/s00432-017-2464-9","article-title":"ROS-modulated therapeutic approaches in cancer treatment","volume":"143","author":"Raza","year":"2017","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Allegra, A., Caserta, S., Genovese, S., Pioggia, G., and Gangemi, S. (2023). Gender differences in oxidative stress in relation to cancer susceptibility and survival. Antioxidants, 12.","DOI":"10.20944\/preprints202305.0677.v1"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.critrevonc.2011.01.004","article-title":"Free radicals in breast carcinogenesis, breast cancer progression and cancer stem cells. Biological bases to develop oxidative-based therapies","volume":"80","author":"Lorente","year":"2011","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1021\/acs.jafc.7b04472","article-title":"Zerumbone, a cyclic sesquiterpene from Zingiber zerumbet induces apoptosis, cell cycle arrest, and antimigratory effects in SW480 colorectal cancer cells","volume":"66","author":"Sithara","year":"2018","journal-title":"J. Agric. Food Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8472","DOI":"10.1021\/acs.jafc.5b02997","article-title":"Composition and tissue-specific distribution of stilbenoids in grape canes are affected by downy mildew pressure in the vineyard","volume":"63","author":"Besseau","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Akinwumi, B.C., Bordun, K.A.M., and Anderson, H.D. (2018). Biological activities of stilbenoids. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030792"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ramawat, K.G., and M\u00e9rillon, J.-M. (2013). Natural Products: Phytochemistry, Botany and Metabolism of Alkaloids, Phenolics and Terpenes, Springer.","DOI":"10.1007\/978-3-642-22144-6"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1039\/c2np20049j","article-title":"Natural stilbenoids: Distribution in the plant kingdom and chemotaxonomic interest in Vitaceae","volume":"29","author":"Riviere","year":"2012","journal-title":"Nat. Prod. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4222","DOI":"10.1021\/jf060160f","article-title":"Comparison of ozone and UV-C treatments on the postharvest stilbenoid monomer, dimer, and trimer induction in var. \u2018Superior\u2019 white table grapes","volume":"54","author":"Cantos","year":"2006","journal-title":"J. Agric. Food Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Courtois, A., Atgi\u00e9, C., Marchal, A., Hornedo-Ortega, R., Lap\u00e8ze, C., Faure, C., Richard, T., and Krisa, S. (2018). Tissular distribution and metabolism of trans-epsilon-viniferin after intraperitoneal injection in rat. Nutrients, 10.","DOI":"10.3390\/nu10111660"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.jpba.2016.11.044","article-title":"A simple and sensitive liquid chromatography-tandem mass spectrometry method for trans-epsilon-viniferin quantification in mouse plasma and its application to a pharmacokinetic study in mice","volume":"134","author":"Kim","year":"2017","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e120722","DOI":"10.1172\/jci.insight.120722","article-title":"SIRT3 diminishes inflammation and mitigates endotoxin-induced acute lung injury","volume":"4","author":"Kurundkar","year":"2019","journal-title":"JCI Insight"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1007\/s10616-015-9863-z","article-title":"Direct and protective effects of single or combined addition of vincristine and \u03b5-viniferin on human HepG2 cellular oxidative stress markers in vitro","volume":"68","author":"Tarhan","year":"2016","journal-title":"Cytotechnology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10084","DOI":"10.1039\/D0FO01932A","article-title":"\u03b5-Viniferin, a promising natural oligostilbene, ameliorates hyperglycemia and hyperlipidemia by activating AMPK in vivo","volume":"11","author":"Liu","year":"2020","journal-title":"Food Funct."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1021\/acs.jnatprod.7b00197","article-title":"Cyperaceae species are potential sources of natural mammalian arginase inhibitors with positive effects on vascular function","volume":"80","author":"Arraki","year":"2017","journal-title":"J. Nat. Prod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.4103\/1673-5374.282264","article-title":"Neuroprotective mechanisms of \u03b5-viniferin in a rotenone-induced cell model of Parkinson\u2019s disease: Significance of SIRT3-mediated FOXO3 deacetylation","volume":"15","author":"Zhang","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"309","DOI":"10.18632\/oncotarget.1480","article-title":"Apoptosis inducers in chronic lymphocytic leukemia","volume":"5","author":"Billard","year":"2013","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"166","DOI":"10.5114\/aoms.2020.100777","article-title":"Resveratrol is cytotoxic and acts synergistically with NF-\u03baB inhibition in osteosarcoma MG-63 cells","volume":"17","author":"Xu","year":"2020","journal-title":"Arch. Med. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.imlet.2003.08.005","article-title":"Natural mechanisms protecting against cancer","volume":"90","author":"Lasek","year":"2003","journal-title":"Immunol. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"202","DOI":"10.26650\/IstanbulJPharm.2020.0039","article-title":"Interaction of curcumin on cisplatin cytotoxicity in HeLa and HepG2 carcinoma cells","volume":"50","author":"Becit","year":"2020","journal-title":"Istanb. J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.fct.2013.01.029","article-title":"Assessment of polyphenolic content, antioxidant activity, protection against ROS-induced DNA damage and anticancer activity of Vitis vinifera stem extracts","volume":"61","author":"Apostolou","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"112617","DOI":"10.1016\/j.fct.2021.112617","article-title":"\u03b5-Viniferin and \u03b1-viniferin alone or in combination induced apoptosis and necrosis in osteosarcoma and non-small cell lung cancer cells","volume":"158","author":"Huang","year":"2021","journal-title":"Food Chem. Toxicol."},{"key":"ref_33","unstructured":"Bertino, J.R. (1997). Encyclopedia of Cancer. Encyclopedia of Cancer, Academic Press."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"347","DOI":"10.3109\/10408441003601836","article-title":"The relationship between cisplatin-induced reactive oxygen species, glutathione, and BCL-2 and resistance to cisplatin","volume":"40","author":"Brozovic","year":"2010","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1080\/08880010590964381","article-title":"Severe neurotoxicity, ototoxicity and nephrotoxicity following high-dose cisplatin and amifostine","volume":"22","author":"Sastry","year":"2005","journal-title":"Pediatr. Hematol. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/j.fct.2006.01.013","article-title":"Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: A review of some recent research","volume":"44","author":"Ali","year":"2006","journal-title":"Food Chem. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Silvestrini, A., Meucci, E., Ricerca, B.M., and Mancini, A. (2023). Total Antioxidant Capacity: Biochemical Aspects and Clinical Significance. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310978"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Rosa, A.C., Corsi, D., Cavi, N., Bruni, N., and Dosio, F. (2021). Superoxide dismutase administration: A review of proposed human uses. Molecules, 26.","DOI":"10.3390\/molecules26071844"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"671","DOI":"10.3109\/1354750X.2012.715672","article-title":"Glutathione levels in human tumors","volume":"17","author":"Gamcsik","year":"2012","journal-title":"Biomarkers"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1080\/10715760802317663","article-title":"Glutathione and apoptosis","volume":"42","author":"Circu","year":"2008","journal-title":"Free. Radic. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"853","DOI":"10.2174\/138920006779010601","article-title":"Endogenous glutathione adducts","volume":"7","author":"Blair","year":"2006","journal-title":"Curr. Drug Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.2174\/0929867053764635","article-title":"Metals, toxicity and oxidative stress","volume":"12","author":"Valko","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/0891-5849(91)90192-6","article-title":"Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes","volume":"11","author":"Esterbauer","year":"1991","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1007\/s00405-012-2029-0","article-title":"Reactive oxygen species in apoptosis induced by cisplatin: Review of physiopathological mechanisms in animal models","volume":"269","author":"Casares","year":"2012","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1021\/tx00031a001","article-title":"Mechanisms and biological relevance of lipid peroxidation initiation","volume":"6","author":"Dix","year":"1993","journal-title":"Chem. Res. Toxicol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"a006080","DOI":"10.1101\/cshperspect.a006080","article-title":"Cell death signaling","volume":"7","author":"Green","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/sj.cdd.4402028","article-title":"Apoptosome: A platform for the activation of initiator caspases","volume":"14","author":"Bao","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/nrm2153","article-title":"The apoptosome: Signalling platform of cell death","volume":"8","author":"Riedl","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_49","first-page":"53","article-title":"Combinations of resveratrol, cisplatin and oxaliplatin applied to human ovarian cancer cells","volume":"32","author":"Nessa","year":"2012","journal-title":"Anticancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1007\/s10616-018-0197-5","article-title":"Apoptotic effects of \u03b5-viniferin in combination with cis-platin in C6 cells","volume":"70","year":"2018","journal-title":"Cytotechnology"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Zhang, B., Wang, X.Q., Chen, H., Zheng, Q., and Li, X. (2011). The role of GSH depletion in Resveratrol induced HeLa cell apoptosis. Proceedings of the 2011 IEEE International Conference on Systems Biology (ISB), IEEE.","DOI":"10.1109\/ISB.2011.6033113"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1016\/j.lfs.2007.08.047","article-title":"Evaluation of antitumor effects of two vine stalk oligomers of resveratrol on a panel of lymphoid and myeloid cell lines: Comparison with resveratrol","volume":"81","author":"Barjot","year":"2007","journal-title":"Life Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1002\/ptr.5443","article-title":"The Resveratrol Tetramer r-Viniferin Induces a Cell Cycle Arrest Followed by Apoptosis in the Prostate Cancer Cell Line LNCaP","volume":"29","author":"Empl","year":"2015","journal-title":"Phytother. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.clinbiochem.2005.08.008","article-title":"A new automated colorimetric method for measuring total oxidant status","volume":"38","author":"Erel","year":"2005","journal-title":"Clin. Biochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.clinbiochem.2003.11.015","article-title":"A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation","volume":"37","author":"Erel","year":"2004","journal-title":"Clin. Biochem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/14\/2409\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T04:26:03Z","timestamp":1783657563000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/14\/2409"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,8]]},"references-count":56,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["molecules31142409"],"URL":"https:\/\/doi.org\/10.3390\/molecules31142409","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,8]]}}}