{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T22:37:42Z","timestamp":1785796662218,"version":"3.56.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,4,1]],"date-time":"2023-04-01T00:00:00Z","timestamp":1680307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 CA231210-01A1"],"award-info":[{"award-number":["R01 CA231210-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NCI","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Sulfasalazine (SAS) is a repurposed antitumor drug which inhibits the proliferation and survival of cancer cells by inhibiting the xCT cellular antioxidant system. Recent clinical studies have shown that, due to poor bioavailability, the antitumor effects of SAS monotherapy are minimal. Therefore, we hypothesized that DSF, another repurposed drug that has demonstrated anticancer effects, or its complex with copper (DSF-copper, DSF-Cu) could potentiate the antilung cancer effects of SAS. Exposure of non-small cell lung cancer cells to therapeutically achievable concentrations of SAS-induced low-to-moderate cytotoxic effects (20\u201340% reduction in cell viability) and, unexpectedly, induced the antioxidant protein NRF2 and its downstream effectors xCT and ALDH1A1. However, combinations of SAS and DSF-Cu, but not SAS and DSF, induced a significantly higher cytotoxic effect (64\u201388% reduction in cell viability), apoptosis and generation of mitochondrial reactive oxygen species as compared with SAS or DSF-Cu alone. Moreover, DSF-Cu abrogated SAS-induced NRF2, xCT and ALDH1A1 expression. In a mouse model of lung tumor, SAS + DSF-Cu showed a higher efficacy than the individual drugs in reducing the number and size of tumors as well as the incidence and multiplicity of lung adenocarcinoma. Taken together, our findings indicate that the observed antilung cancer effects of SAS plus DSF-Cu are mediated, at least in part, via impairment of reactive oxygen species defense and \u00adenhancement of oxidative stress and provide evidence for the preventive\/therapeutic potential of this combinatorial approach against lung cancer.<\/jats:p>","DOI":"10.1093\/carcin\/bgad020","type":"journal-article","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T16:08:44Z","timestamp":1681402124000},"page":"291-303","source":"Crossref","is-referenced-by-count":17,"title":["Inhibition of lung adenocarcinoma by combinations of sulfasalazine (SAS) and disulfiram-copper (DSF-Cu) in cell line models and mice"],"prefix":"10.1093","volume":"44","author":[{"given":"Alireza Jian","family":"Bagherpoor","sequence":"first","affiliation":[{"name":"Masonic Cancer Center , Minneapolis, MN 55455 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Shameem","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center , Minneapolis, MN 55455 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianghua","family":"Luo","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center , Minneapolis, MN 55455 , USA"},{"name":"Division of Biostatistics, School of Public Health , Minneapolis, MN 55455 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davis","family":"Seelig","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center , Minneapolis, MN 55455 , USA"},{"name":"College of Veterinary Medicine, University of Minnesota , Saint Paul, MN 55108 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0089-939X","authenticated-orcid":false,"given":"Fekadu","family":"Kassie","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center , Minneapolis, MN 55455 , USA"},{"name":"College of Veterinary Medicine, University of Minnesota , Saint Paul, MN 55108 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,4,13]]},"reference":[{"key":"2023110912084596300_CIT0001","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"2023110912084596300_CIT0002","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.cell.2017.06.009","article-title":"RAS proteins and their regulators in human disease","volume":"170","author":"Simanshu","year":"2017","journal-title":"Cell"},{"key":"2023110912084596300_CIT0003","doi-asserted-by":"crossref","first-page":"8788","DOI":"10.1073\/pnas.1003428107","article-title":"Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity","volume":"107","author":"Weinberg","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023110912084596300_CIT0004","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nature10189","article-title":"Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis","volume":"475","author":"DeNicola","year":"2011","journal-title":"Nature"},{"key":"2023110912084596300_CIT0005","doi-asserted-by":"crossref","first-page":"9433","DOI":"10.1073\/pnas.1821323116","article-title":"Cystine\/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance","volume":"116","author":"Lim","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023110912084596300_CIT0006","first-page":"12","article-title":"Amino acid transporter SLC7A11\/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer","volume":"38","author":"Koppula","year":"2018","journal-title":"Cancer Commun. (Lond.)"},{"key":"2023110912084596300_CIT0007","doi-asserted-by":"crossref","first-page":"5007","DOI":"10.1038\/s41388-018-0307-z","article-title":"xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression","volume":"37","author":"Ji","year":"2018","journal-title":"Oncogene"},{"key":"2023110912084596300_CIT0008","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.ccr.2011.01.038","article-title":"CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(\u2212) and thereby promotes tumor growth","volume":"19","author":"Ishimoto","year":"2011","journal-title":"Cancer Cell"},{"key":"2023110912084596300_CIT0009","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1172\/JCI124049","article-title":"Suppression of the SLC7A11\/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma","volume":"130","author":"Hu","year":"2020","journal-title":"J. Clin. Invest."},{"key":"2023110912084596300_CIT0010","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1158\/0008-5472.CAN-12-3609-T","article-title":"xCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma","volume":"73","author":"Yoshikawa","year":"2013","journal-title":"Cancer Res."},{"key":"2023110912084596300_CIT0011","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1111\/cas.13309","article-title":"Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer","volume":"108","author":"Otsubo","year":"2017","journal-title":"Cancer Sci."},{"key":"2023110912084596300_CIT0012","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s10120-016-0610-8","article-title":"Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205)","volume":"20","author":"Shitara","year":"2017","journal-title":"Gastric Cancer"},{"key":"2023110912084596300_CIT0013","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1186\/1471-2407-9-372","article-title":"Early termination of ISRCTN45828668, a phase \u00bd prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults","volume":"9","author":"Robe","year":"2018","journal-title":"BMC Cancer"},{"key":"2023110912084596300_CIT0014","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1093\/cvr\/cvp072","article-title":"Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signaling, leading to control of neointimal hyperplasia","volume":"82","author":"Kim","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"2023110912084596300_CIT0015","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ccell.2018.03.022","article-title":"NRF2 and the hallmarks of cancer","volume":"34","author":"Rojo de la Vega","year":"2018","journal-title":"Cancer Cell"},{"key":"2023110912084596300_CIT0016","doi-asserted-by":"crossref","first-page":"3996","DOI":"10.1158\/0008-5472.CAN-09-3752","article-title":"Disulfiram treatment facilitates phosphoinositide 3-kinase inhibition in human breast cancer cells in vitro and in vivo","volume":"70","author":"Zhang","year":"2010","journal-title":"Cancer Res."},{"key":"2023110912084596300_CIT0017","doi-asserted-by":"crossref","first-page":"10425","DOI":"10.1158\/0008-5472.CAN-06-2126","article-title":"Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity","volume":"66","author":"Chen","year":"2006","journal-title":"Cancer Res."},{"key":"2023110912084596300_CIT0018","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/nature25016","article-title":"Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4","volume":"552","author":"Skrott","year":"2017","journal-title":"Nature"},{"key":"2023110912084596300_CIT0019","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1186\/1479-5876-12-163","article-title":"Disulfiram targeting lymphoid malignant cell lines via ROS-JNK activation as well as Nrf2 and NF-kB pathway inhibition","volume":"12","author":"Zha","year":"2014","journal-title":"Transl. Med."},{"key":"2023110912084596300_CIT0020","doi-asserted-by":"crossref","first-page":"e2797","DOI":"10.1038\/cddis.2017.176","article-title":"Disulfiram\/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-\u03baB and Nrf2","volume":"8","author":"Xu","year":"2017","journal-title":"Cell Death Dis."},{"key":"2023110912084596300_CIT0021","first-page":"1","article-title":"Personal habits and indoor combustions. Volume 100 E. A review of human carcinogens","volume":"100","author":"IARC Working Group on the Evaluation of Carcinogenic Risks to Humans","year":"2012","journal-title":"IARC Monogr. Eval. Carcinogen. Risks Hum."},{"key":"2023110912084596300_CIT0022","first-page":"2877","article-title":"K-ras mutations in lung tumors from NNK-treated mice with lipopolysaccharide-elicited lung inflammation","volume":"31","author":"Keohavong","year":"2011","journal-title":"Anticancer Res."},{"key":"2023110912084596300_CIT0023","doi-asserted-by":"crossref","first-page":"7122","DOI":"10.7150\/thno.35729","article-title":"Aldehyde dehydrogenase 1A1 confers erlotinib resistance via facilitating the reactive oxygen species-reactive carbonyl species metabolic pathway in lung adenocarcinomas","volume":"9","author":"Lei","year":"2019","journal-title":"Theranostics"},{"key":"2023110912084596300_CIT0024","doi-asserted-by":"crossref","first-page":"W739","DOI":"10.1093\/nar\/gkac382","article-title":"SynergyFinder 3.0: an interactive analysis and consensus interpretation of multidrug synergies across multiple samples","volume":"50","author":"Ianevski","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"2023110912084596300_CIT0025","doi-asserted-by":"crossref","first-page":"26927","DOI":"10.18632\/oncotarget.15879","article-title":"Triptolide suppresses the in vitro and in vivo growth of lung cancer cells by targeting hyaluronan-CD44\/RHAMM signaling","volume":"8","author":"Song","year":"2017","journal-title":"Oncotarget"},{"key":"2023110912084596300_CIT0026","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1093\/carcin\/bgac019","article-title":"Combinatory lung tumor inhibition by myo-inositol and iloprost\/rapamycin: association with immunomodulation","volume":"43","author":"Kassie","year":"2022","journal-title":"Carcinogenesis"},{"key":"2023110912084596300_CIT0027","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s40170-021-00249-6","article-title":"Sulfasalazine modifies metabolic profiles and enhances cisplatin chemosensitivity on cholangiocarcinoma cells in in vitro and in vivo models","volume":"9","author":"Thanee","year":"2021","journal-title":"Cancer Metab."},{"key":"2023110912084596300_CIT0028","doi-asserted-by":"crossref","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":"2017","journal-title":"Clin. Cancer Res."},{"key":"2023110912084596300_CIT0029","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"Reagan-Shaw","year":"2008","journal-title":"FASEB J."},{"key":"2023110912084596300_CIT0030","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s11060-016-2104-2","article-title":"A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy","volume":"128","author":"Huang","year":"2016","journal-title":"J. Neurooncol."},{"key":"2023110912084596300_CIT0031","doi-asserted-by":"crossref","first-page":"867S","DOI":"10.1093\/ajcn\/88.3.867S","article-title":"Estimating risk from copper excess in human populations","volume":"88","author":"Uauy","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"2023110912084596300_CIT0032","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1093\/carcin\/bgr010","article-title":"Enhanced inhibition of lung adenocarcinoma by combinatorial treatment with indole-3-carbinol and silibinin in A\/J mice","volume":"32","author":"Dagne","year":"2011","journal-title":"Carcinogenesis"},{"key":"2023110912084596300_CIT0033","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1158\/0008-5472.CAN-03-3376","article-title":"Classification of proliferative pulmonary lesions of the mouse: recommendations of the mouse models of human cancers consortium","volume":"64","author":"Nikitin","year":"2004","journal-title":"Cancer Res."},{"key":"2023110912084596300_CIT0034","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1016\/j.bbamcr.2016.09.012","article-title":"Activation of apoptosis signaling pathways by reactive oxygen species.","volume":"1863","author":"Redza-Dutordoir","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"2023110912084596300_CIT0035","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1159\/000047804","article-title":"Reactive oxygen species as intracellular messengers during cell growth and differentiation","volume":"11","author":"Sauer","year":"2001","journal-title":"Cell. Physiol. Biochem."},{"key":"2023110912084596300_CIT0036","doi-asserted-by":"crossref","first-page":"e543","DOI":"10.1016\/S1470-2045(20)30610-0","article-title":"Drug repurposing in oncology","volume":"21","author":"Frantzi","year":"2020","journal-title":"Lancet Oncol."},{"key":"2023110912084596300_CIT0037","first-page":"107","article-title":"Ulcerative colitis in children. Levels of salicylazosulfapyridine and sulfapyridine during treatment [Spanish]","volume":"18","author":"Guastavino","year":"1988","journal-title":"Acta Gastroenterol. Latinoam."},{"key":"2023110912084596300_CIT0038","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1007\/s40199-019-00308-w","article-title":"Recent advances in the delivery of disulfiram: a critical analysis of promising approaches to improve its pharmacokinetic profile and anticancer efficacy","volume":"27","author":"Farooq","year":"2019","journal-title":"Daru"},{"key":"2023110912084596300_CIT0039","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1021\/mp050113v","article-title":"Breast cancer resistance protein (Bcrp\/abcg2) is a major determinant of sulfasalazine absorption and elimination in the mouse","volume":"3","author":"Zaher","year":"2006","journal-title":"Mol. Pharm."},{"key":"2023110912084596300_CIT0040","doi-asserted-by":"crossref","first-page":"4521","DOI":"10.7150\/jca.34374","article-title":"The Power of phytochemicals combination in cancer chemoprevention","volume":"11","author":"Rizeq","year":"2020","journal-title":"J. Cancer"},{"key":"2023110912084596300_CIT0041","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/s41416-019-0660-x","article-title":"Activation of the reverse transsulfuration pathway through NRF2\/CBS confers erastin-induced ferroptosis resistance","volume":"122","author":"Liu","year":"2020","journal-title":"Br. J. Cancer"},{"key":"2023110912084596300_CIT0042","doi-asserted-by":"crossref","first-page":"33832","DOI":"10.18632\/oncotarget.26112","article-title":"Synthetic lethality of the ALDH3A1 inhibitor dyclonine and xCT inhibitors in glutathione deficiency-resistant cancer cells","volume":"9","author":"Okazaki","year":"2018","journal-title":"Oncotarget"},{"key":"2023110912084596300_CIT0043","doi-asserted-by":"crossref","first-page":"303","DOI":"10.2217\/nnm-2021-0374","article-title":"Copper-induced tumor cell death mechanisms and antitumor theragnostic applications of copper complexes","volume":"17","author":"Jiang","year":"2022","journal-title":"Nanomedicine (Lond.)"},{"key":"2023110912084596300_CIT0044","doi-asserted-by":"crossref","first-page":"741316","DOI":"10.3389\/fmolb.2021.741316","article-title":"Recent advances in repurposing disulfiram and disulfiram derivatives as copper-dependent anticancer agents","volume":"8","author":"Kannappan","year":"2021","journal-title":"Front Mol. Biosci."},{"key":"2023110912084596300_CIT0045","first-page":"3163","article-title":"Role of the alveolar type II cell in the development and progression of pulmonary tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in the A\/J mouse","volume":"52","author":"Belinsky","year":"1992","journal-title":"Cancer Res."},{"key":"2023110912084596300_CIT0046","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/nrclinonc.2013.64","article-title":"Lung cancer chemoprevention: current status and future prospects","volume":"10","author":"Keith","year":"2013","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"2023110912084596300_CIT0047","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1158\/1078-0432.CCR-07-1757","article-title":"Quantitative monitoring of adenocarcinoma development in rodents by magnetic resonance imaging","volume":"14","author":"Garbow","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"2023110912084596300_CIT0048","doi-asserted-by":"crossref","first-page":"8548","DOI":"10.1158\/0008-5472.CAN-05-0237","article-title":"Phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates inhibit malignant progression of lung adenomas induced by tobacco carcinogens in A\/J mice","volume":"65","author":"Conaway","year":"2005","journal-title":"Cancer Res."}],"container-title":["Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/carcin\/advance-article-pdf\/doi\/10.1093\/carcin\/bgad020\/50377246\/bgad020.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/carcin\/article-pdf\/44\/4\/291\/52974887\/bgad020.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/carcin\/article-pdf\/44\/4\/291\/52974887\/bgad020.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T12:11:31Z","timestamp":1699531891000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/carcin\/article\/44\/4\/291\/7117639"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,1]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4,13]]},"published-print":{"date-parts":[[2023,6,24]]}},"URL":"https:\/\/doi.org\/10.1093\/carcin\/bgad020","relation":{},"ISSN":["0143-3334","1460-2180"],"issn-type":[{"value":"0143-3334","type":"print"},{"value":"1460-2180","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,4,1]]},"published":{"date-parts":[[2023,4,1]]}}}