{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:18:32Z","timestamp":1788218312200,"version":"build-2803163510"},"reference-count":29,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002301","name":"Eesti Teadusagentuur","doi-asserted-by":"publisher","award":["PRG1289"],"award-info":[{"award-number":["PRG1289"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Copper homeostasis is essential for neuronal function, and its dysregulation has been implicated in neurodegenerative disorders. In particular, reduced intracellular copper levels alongside with elevated extracellular copper concentrations have been associated with Alzheimer\u2019s disease (AD). Therefore, strategies aimed at restoring intracellular copper levels represent a potential therapeutic approach. In this study, we investigated the effects of selected copper-binding compounds\u2500\u03b1-lipoic acid (LA), elesclomol (ES), disulfiram (DSF), thiourea (TU), and triapine (3-AP)\u2500on copper uptake and cytotoxicity in SH-SY5Y wild-type (WT) and CTR1-deficient (CTR1\u2013\/\u2013) cells. Intracellular copper levels were quantified using inductively coupled plasma mass spectrometry (ICP-MS), and cell viability was assessed by using propidium iodide assay under various treatment conditions. Among the tested compounds, LA, ES, and DSF significantly increased intracellular copper levels in both WT and CTR1\u2013\/\u2013 cells, whereas TU and 3-AP did not enhance copper accumulation beyond copper-only treatment. Notably, CTR1\u2013\/\u2013 cells exhibited reduced sensitivity to copper-associated toxicity compared to WT cells. Under copper-supplemented conditions, DSF and ES displayed concentration-dependent cytotoxicity, while LA and TU induced only mild effects. In contrast, 3-AP toxicity was abolished in the presence of copper. Furthermore, cotreatment with LA and copper increased cell proliferation and promoted differentiation-associated morphological changes in CTR1\u2013\/\u2013 cells. Overall, our results demonstrate that copper ionophores can enhance intracellular copper levels dependently and independently of CTR1, with distinct effects on cell viability. Among the tested compounds, LA and DSF showed a favorable profile by increasing copper levels while maintaining low cytotoxicity, highlighting their potential for modulating cellular copper homeostasis.<\/jats:p>","DOI":"10.1021\/acsomega.6c04498","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T21:02:09Z","timestamp":1786395729000},"page":"49807-49814","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Effects\nof Copper Ionophores on Intracellular\nCopper and Cell Viability in Wild-Type and CTR1-Deficient SH-SY5Y\nCells"],"prefix":"10.1021","volume":"11","author":[{"given":"Anette","family":"Reinapu","sequence":"first","affiliation":[{"name":"Tallinn University of Technology , , Akadeemia tee 15 , ,","place":["Tallinn, Estonia, 12618"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3949-2623","authenticated-orcid":true,"given":"Sigrid","family":"Kirss","sequence":"additional","affiliation":[{"name":"Tallinn University of Technology , , Akadeemia tee 15 , ,","place":["Tallinn, Estonia, 12618"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vello","family":"To\u0303ugu","sequence":"additional","affiliation":[{"name":"Tallinn University of Technology , , Akadeemia tee 15 , ,","place":["Tallinn, Estonia, 12618"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3505-3466","authenticated-orcid":true,"given":"Peep","family":"Palumaa","sequence":"additional","affiliation":[{"name":"Tallinn University of Technology , , Akadeemia tee 15 , ,","place":["Tallinn, Estonia, 12618"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"issue":"1","key":"2026083119115040300_cit1","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1152\/physrev.00011.2024","article-title":"Mammalian copper homeostasis: physiological roles and\nmolecular mechanisms","volume":"105","author":"Lutsenko","year":"2025","journal-title":"Physiol. 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Alzheimer\u2019s Dis."},{"issue":"7","key":"2026083119115040300_cit4","doi-asserted-by":"publisher","DOI":"10.3390\/biom11070960","article-title":"Copper Imbalance in\nAlzheimer\u2019s Disease: Meta-Analysis of Serum, Plasma, and Brain\nSpecimens, and Replication Study Evaluating ATP7B Gene Variants","volume":"11","author":"Squitti","year":"2021","journal-title":"Biomolecules"},{"issue":"3","key":"2026083119115040300_cit5","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1021\/envhealth.4c00175","article-title":"Disruption of Copper Redox Balance\nand Dysfunction under In Vivo and In Vitro Alzheimer\u2019s Disease\nModels","volume":"3","author":"Xia","year":"2025","journal-title":"Environ. 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Gastrointest.\nLiver Physiol."},{"issue":"8","key":"2026083119115040300_cit28","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1039\/c5mt00097a","article-title":"Copper uptake by DMT1:\na compensatory mechanism for CTR1 deficiency in human umbilical vein\nendothelial cells","volume":"7","author":"Lin","year":"2015","journal-title":"Metallomics"},{"key":"2026083119115040300_cit29","unstructured":"Lane, A. R.; Scher, N. E.; Bhattacharjee, S.; et al.\n          Adaptive\nprotein synthesis in genetic models of copper deficiency and childhood\nneurodegeneration\n          bioRxiv\n          2024."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c04498","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/33\/49807\/66481378\/acsomega.6c04498.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/33\/49807\/66481378\/acsomega.6c04498.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:11:59Z","timestamp":1788217919000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/33\/49807\/5251715\/Distinct-Effects-of-Copper-Ionophores-on"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":29,"journal-issue":{"issue":"33","published-online":{"date-parts":[[2026,8,10]]},"published-print":{"date-parts":[[2026,8,25]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c04498","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]}}}