{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T21:03:22Z","timestamp":1790283802111,"version":"4.1.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T00:00:00Z","timestamp":1713916800000},"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. Pharmacol."],"abstract":"<jats:p>The development of effective therapy for eradicating glioblastoma stem cells remains a major challenge due to their aggressive growth, chemoresistance and radioresistance which are mainly conferred by aldehyde dehydrogenase (ALDH)1A1. The latter is the main stemness mediator via enhancing signaling pathways of Wnt\/\u03b2-catenin, phosphatidylinositol 3-kinase\/AKT, and hypoxia. Furthermore, ALDH1A1 mediates therapeutic resistance by inactivating drugs, stimulating the expression of drug efflux transporters, and detoxifying reactive radical species, thereby apoptosis arresting. Recent reports disclosed the potent and broad-spectrum anticancer activities of the unique nanocomplexes of diethyldithiocarbamate (DE, ALDH1A1 inhibitor) with ferrous oxide nanoparticles (FeO NPs) mainly conferred by inducing lipid peroxidation-dependent non-apoptotic pathways (iron accumulation-triggered ferroptosis), was reported. Accordingly, the anti-stemness activity of nanocomplexes (DE-FeO NPs) was investigated against human and mouse glioma stem cells (GSCs) and radioresistant GSCs (GSCs-RR). DE-FeO NPs exhibited the strongest growth inhibition effect on the treated human GSCs (MGG18 and JX39P), mouse GSCs (GS and PDGF-GSC) and their radioresistant cells (IC<jats:sub>50<\/jats:sub> \u2264 70 and 161\u00a0\u03bcg\/mL, respectively). DE-FeO NPs also revealed a higher inhibitory impact than standard chemotherapy (temozolomide, TMZ) on self-renewal, cancer repopulation, chemoresistance, and radioresistance potentials. Besides, DE-FeO NPs surpassed TMZ regarding the effect on relative expression of all studied stemness genes, as well as relative p-AKT\/AKT ratio in the treated MGG18, GS and their radioresistant (MGG18-RR and GS-RR). This potent anti-stemness influence is primarily attributed to ALDH1A1 inhibition and ferroptosis induction, as confirmed by significant elevation of cellular reactive oxygen species and lipid peroxidation with significant depletion of glutathione and glutathione peroxidase 4. DE-FeO NPs recorded the optimal Log<jats:italic>P<\/jats:italic> value for crossing the blood brain barrier. This <jats:italic>in vitro<\/jats:italic> novel study declared the potency of DE-FeO NPs for collapsing GSCs and GSCs-RR with improving their sensitivity to chemotherapy and radiotherapy, indicating that DE-FeO NPs may be a promising remedy for GBM. Glioma animal models will be needed for in-depth studies on its safe effectiveness.<\/jats:p>","DOI":"10.3389\/fphar.2024.1363511","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T04:23:31Z","timestamp":1713932611000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Diethyldithiocarbamate-ferrous oxide nanoparticles inhibit human and mouse glioblastoma stemness: aldehyde dehydrogenase 1A1 suppression and ferroptosis induction"],"prefix":"10.3389","volume":"15","author":[{"given":"Marwa M.","family":"Abu-Serie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Osuka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamiaa A.","family":"Heikal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Teleb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Assem","family":"Barakat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Dudeja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,4,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4617","DOI":"10.1038\/s41598-018-22915-4","article-title":"Evaluation of the selective toxic effect of the charge switchable diethyldithiocarbamate-loaded nanoparticles between hepatic normal and cancerous cells","volume":"8","author":"Abu-Serie","year":"2018","journal-title":"Sci. Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1089667","DOI":"10.3389\/fphar.2022.1089667","article-title":"Targeted ferroptotic potency of ferrous oxide nanoparticles-diethyldithiocarbamate nanocomplex on the metastatic liver cancer","volume":"13","author":"Abu-Serie","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"122208","DOI":"10.1016\/j.ijpharm.2022.122208","article-title":"Anti-metastatic breast cancer potential of novel nanocomplexes of diethyldithiocarbamate and green chemically synthesized iron oxide nanoparticles","volume":"627","author":"Abu-Serie","year":"2022","journal-title":"Int. J. Pharm."},{"key":"B4","doi-asserted-by":"publisher","first-page":"3529","DOI":"10.1038\/s41598-023-30553-8","article-title":"A comparative study of smart nanoformulations of diethyldithiocarbamate with Cu4O3 nanoparticles or zinc oxide nanoparticles for efficient eradication of metastatic breast cancer","volume":"13","author":"Abu-Serie","year":"2023","journal-title":"Sci. Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.2217\/nnm-2021-0013","article-title":"Pluronic F127 micelles improve the stability and enhance the anticancer stem cell efficacy of citral in breast cancer","volume":"16","author":"Abu-Serie","year":"2021","journal-title":"Nanomedicine (Lond.)"},{"key":"B6","doi-asserted-by":"publisher","first-page":"121149","DOI":"10.1016\/j.ijpharm.2021.121149","article-title":"Novel nanoformulated diethyldithiocarbamate complexes with biosynthesized or green chemosynthesized copper oxide nanoparticles: an in vitro comparative anticancer study","volume":"609","author":"Abu-Serie","year":"2021","journal-title":"Int. J. Pharm."},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.2217\/nnm-2024-0007","article-title":"Synergistic eradicating impact of 5-fluouracil with FeO nanoparticles-diethyldithiocarbamate in colon cancer spheroids","author":"Abu-Serie","year":"2024","journal-title":"Nanomedicine (Lond)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s13287-021-02231-x","article-title":"Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives","volume":"12","author":"Alves","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1038\/cdd.2014.31","article-title":"Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy","volume":"21","author":"Auffinger","year":"2014","journal-title":"Cell Death Differ."},{"key":"B9","doi-asserted-by":"publisher","first-page":"36","DOI":"10.3892\/ol.2023.14169","article-title":"Research progress on ferroptosis in gliomas (Review)","volume":"27","author":"Bo","year":"2024","journal-title":"Oncol. Lett."},{"key":"B10","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.stem.2010.01.001","article-title":"Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells","volume":"6","author":"Charles","year":"2010","journal-title":"Cell Stem Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s12929-021-00717-7","article-title":"Dissecting the mechanism of temozolomide resistance and its association with the regulatory roles of intracellular reactive oxygen species in glioblastoma","volume":"28","author":"Chien","year":"2021","journal-title":"J. Biomed. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"856","DOI":"10.3171\/JNS\/2008\/109\/11\/0856","article-title":"Characterization of a side population of astrocytoma cells in response to temozolomide","volume":"109","author":"Chua","year":"2008","journal-title":"J. Neurosurg."},{"key":"B13","doi-asserted-by":"publisher","first-page":"26","DOI":"10.20517\/cdr.2019.70","article-title":"How to conjugate the stemness marker ALDH1A1 with tumor angiogenesis, progression, and drug resistance","volume":"3","author":"Ciccone","year":"2020","journal-title":"Cancer Drug Resist"},{"key":"B14","doi-asserted-by":"publisher","first-page":"110350","DOI":"10.1016\/j.cellsig.2022.110350","article-title":"Crosstalk between PI3K\/AKT\/mTOR and WNT\/\u03b2-Catenin signaling in GBM- Could combination therapy checkmate the collusion?","volume":"95","author":"Daisy Precilla","year":"2022","journal-title":"Cell. Signal."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.2147\/JHC.S336858","article-title":"Wnt\/\u03b2-Catenin signaling as a driver of hepatocellular carcinoma progression: an emphasis on molecular pathways","volume":"8","author":"Deldar Abad Paskeh","year":"2021","journal-title":"J. Hepatocell. Carcinoma."},{"key":"B16","doi-asserted-by":"publisher","first-page":"21873","DOI":"10.1038\/s41598-020-78788-z","article-title":"Combined PI3K\u03b1-mTOR targeting of glioma stem cells","volume":"10","author":"Eckerdt","year":"2020","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/0003-9861(59)90090-6","article-title":"Tissue sulfhydryl groups","volume":"82","author":"Ellman","year":"1959","journal-title":"Arch. Biochem. Biophys."},{"key":"B18","volume-title":"Substituent constant for correlation analysis in chemistry and biology","author":"Hansch","year":"1980"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.18632\/oncotarget.707","article-title":"High-throughput chemical screens identify disulfiram as an inhibitor of human glioblastoma stem cells","volume":"3","author":"Hothi","year":"2012","journal-title":"Oncotarget"},{"key":"B20","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1007\/BF02623889","article-title":"Lipid peroxidation in hepatocyte cell cultures: modulation by free radical scavengers and iron","volume":"24","author":"Innes","year":"1988","journal-title":"Vitro Cell Dev. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.pep.2008.07.014","article-title":"New strategies for the isolation and activity determination of naturally occurring type-4 glutathione peroxidase","volume":"62","author":"Kernstock","year":"2008","journal-title":"Protein Expr. Purif."},{"key":"B22","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/s41420-024-01873-z","article-title":"CREB5 promotes the proliferation and self-renewal ability of glioma stem cells","volume":"10","author":"Kim","year":"2024","journal-title":"Cell Death Discov."},{"key":"B23","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1124\/pr.111.005538","article-title":"Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application","volume":"64","author":"Koppaka","year":"2012","journal-title":"Pharmacol. Rev."},{"key":"B24","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1007\/s13238-020-00789-5","article-title":"Cystine transporter slc7a11\/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy","volume":"12","author":"Koppula","year":"2021","journal-title":"Protein Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"33440","DOI":"10.18632\/oncotarget.7961","article-title":"PI3K\/Akt\/mTOR signaling pathway and targeted therapy for glioblastoma","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"B26","doi-asserted-by":"publisher","first-page":"3860","DOI":"10.1158\/1078-0432.CCR-15-1798","article-title":"Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of glioblastoma","volume":"22","author":"Lun","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2123","DOI":"10.3390\/antiox11112123","article-title":"Ferroptosis and its potential role in glioma: from molecular mechanisms to therapeutic opportunities","volume":"11","author":"Luo","year":"2022","journal-title":"Antioxidants (Basel)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e136098","DOI":"10.1172\/JCI136098","article-title":"N-cadherin upregulation mediates adaptive radioresistance in glioblastoma","volume":"131","author":"Osuka","year":"2021","journal-title":"J. Clin. Invest."},{"key":"B29","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1602\/neurorx.2.4.541","article-title":"Medicinal chemical properties of successful central nervous system drugs","volume":"2","author":"Pajouhesh","year":"2005","journal-title":"NeuroRx"},{"key":"B30","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1093\/carcin\/bgt366","article-title":"Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage","volume":"35","author":"Paranjpe","year":"2014","journal-title":"Carcinogenesis"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1002\/bit.26973","article-title":"Quantitative characterization of the regulation of iron metabolism in glioblastoma stem-like cells using magnetophoresis","volume":"116","author":"Park","year":"2019","journal-title":"Biotechnol. Bioeng."},{"key":"B32","doi-asserted-by":"publisher","first-page":"110120","DOI":"10.1016\/j.cellsig.2021.110120","article-title":"Aldehyde dehydrogenase 1A1 and 1A3 isoforms - mechanism of activation and regulation in cancer","volume":"87","author":"Poturnajova","year":"2021","journal-title":"Cell Signal"},{"key":"B33","doi-asserted-by":"publisher","first-page":"850","DOI":"10.20517\/cdr.2022.20","article-title":"Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces","volume":"5","author":"Safa","year":"2022","journal-title":"Cancer Drug Resist"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e66","DOI":"10.1002\/mog2.66","article-title":"The hidden architects of glioblastoma multiforme: glioma stem cells","volume":"3","author":"Sahoo","year":"2024","journal-title":"MedComm. Oncol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1093\/neuonc\/nos270","article-title":"Aldehyde dehydrogenase 1A1-a new mediator of resistance to temozolomide in glioblastoma","volume":"14","author":"Sch\u00e4fer","year":"2012","journal-title":"Neuro. Oncol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"6741","DOI":"10.1002\/jcb.27972","article-title":"A curcumin derivative hydrazinobenzoylcurcumin suppresses stem-like features of glioblastoma cells by targeting Ca2+\/calmodulin-dependent protein kinase II","volume":"120","author":"Shin","year":"2019","journal-title":"J. Cell Biochem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"17","DOI":"10.20517\/cdr.2020.79","article-title":"Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review","volume":"4","author":"Singh","year":"2021","journal-title":"Cancer Drug Resist"},{"key":"B38","doi-asserted-by":"publisher","first-page":"843","DOI":"10.3349\/ymj.2021.62.9.843","article-title":"Temozolomide drives ferroptosis via a DMT1-dependent pathway in glioblastoma cells","volume":"62","author":"Song","year":"2021","journal-title":"Yonsei Med. J."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e148717","DOI":"10.1172\/jci.insight.148717","article-title":"An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases","volume":"7","author":"Stackhouse","year":"2022","journal-title":"JCI Insight"},{"key":"B40","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/S1470-2045(09)70025-7","article-title":"Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial","volume":"10","author":"Stupp","year":"2009","journal-title":"Lancet Oncol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"701291","DOI":"10.3389\/fonc.2021.701291","article-title":"Targeting glioblastoma stem cells: a review on biomarkers, signal pathways and targeted therapy","volume":"11","author":"Tang","year":"2021","journal-title":"Front. Oncol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"032059","DOI":"10.1088\/1742-6596\/1073\/3\/032059","article-title":"Relative expression of aldehyde dehydrogenase 1 family member A1 in different malignancies of human glioma cells","volume":"1073","author":"Tango","year":"2018","journal-title":"J. Phys. Conf. Ser."},{"key":"B43","doi-asserted-by":"publisher","first-page":"339","DOI":"10.3390\/biomedicines8090339","article-title":"Molecular mechanisms of KDELC2 on glioblastoma tumorigenesis and temozolomide resistance","volume":"8","author":"Tsai","year":"2022","journal-title":"Biomedicines"},{"key":"B44","doi-asserted-by":"publisher","first-page":"e05442","DOI":"10.1016\/j.heliyon.2020.e05442","article-title":"Association of ALDH1A1-NEK-2 axis in cisplatin resistance in ovarian cancer cells","volume":"6","author":"Uddin","year":"2020","journal-title":"Heliyon"},{"key":"B45","doi-asserted-by":"publisher","first-page":"103","DOI":"10.2119\/molmed.2010.00062","article-title":"Inhibition of Sonic hedgehog and Notch pathways enhances sensitivity of CD133(+) glioma stem cells to temozolomide therapy","volume":"17","author":"Ulasov","year":"2011","journal-title":"Mol. Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"3904645","DOI":"10.1155\/2019\/3904645","article-title":"Aldehyde dehydrogenases: not just markers, but functional regulators of stem cells","volume":"2019","author":"Vassalli","year":"2019","journal-title":"Stem Cells Int."},{"key":"B47","doi-asserted-by":"publisher","first-page":"3472","DOI":"10.1158\/0008-5472.CAN-08-3886","article-title":"Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors","volume":"69","author":"Wakimoto","year":"2009","journal-title":"Cancer Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1093\/neuonc\/nor195","article-title":"Maintenance of primary tumor phenotype and genotype in glioblastoma stem cells","volume":"14","author":"Wakimoto","year":"2012","journal-title":"Neuro. Oncol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1346585","DOI":"10.3389\/fimmu.2024.1346585","article-title":"Deciphering the link: ferroptosis and its role in glioma","volume":"15","author":"Wang","year":"2024","journal-title":"Front. Immunol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"109246","DOI":"10.1016\/j.inoche.2022.109246","article-title":"A facile synthesis of Cu(II) diethyldithiocarbamate from monovalent copper-cysteamine and disulfiram","volume":"137","author":"Wang","year":"2022","journal-title":"Inorg. Chem. Commun."},{"key":"B51","doi-asserted-by":"publisher","first-page":"109940","DOI":"10.1016\/j.biopha.2020.109940","article-title":"ALDH1A1 maintains the cancer stem-like cells properties of esophageal squamous cell carcinoma by activating the AKT signal pathway and interacting with \u03b2-catenin","volume":"125","author":"Wang","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1026278","DOI":"10.3389\/fonc.2022.1026278","article-title":"ALDH1: a potential therapeutic target for cancer stem cells in solid tumors","volume":"12","author":"Wei","year":"2022","journal-title":"Front. Oncol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.jconrel.2024.01.004","article-title":"NIR-promoted ferrous ion regeneration enhances ferroptosis for glioblastoma treatment","volume":"368","author":"Xue","year":"2024","journal-title":"J. Control. release."},{"key":"B54","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/s41392-020-0110-5","article-title":"Targeting cancer stem cell pathways for cancer therapy","volume":"5","author":"Yang","year":"2020","journal-title":"Signal Transduct. Target Ther."},{"key":"B55","doi-asserted-by":"publisher","first-page":"933655","DOI":"10.3389\/fphar.2022.933655","article-title":"Disulfiram in glioma: literature review of drug repurposing","volume":"13","author":"Zhong","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"974156","DOI":"10.3389\/fmolb.2022.974156","article-title":"Emerging role of ferroptosis in glioblastoma: therapeutic opportunities and challenges","volume":"9","author":"Zhuo","year":"2022","journal-title":"Front. Mol. Biosci."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1363511\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T04:23:35Z","timestamp":1713932615000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1363511\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,24]]},"references-count":57,"alternative-id":["10.3389\/fphar.2024.1363511"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1363511","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,24]]},"article-number":"1363511"}}